MXPA04008858A - Carbamates as hiv protease inhibitors. - Google Patents

Carbamates as hiv protease inhibitors.

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Publication number
MXPA04008858A
MXPA04008858A MXPA04008858A MXPA04008858A MXPA04008858A MX PA04008858 A MXPA04008858 A MX PA04008858A MX PA04008858 A MXPA04008858 A MX PA04008858A MX PA04008858 A MXPA04008858 A MX PA04008858A MX PA04008858 A MXPA04008858 A MX PA04008858A
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Mexico
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compound
group
mmol
compound according
hiv
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MXPA04008858A
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Spanish (es)
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Devasamudram Thippeswamy
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Board Trustees Of The Universi
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Publication of MXPA04008858A publication Critical patent/MXPA04008858A/en

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
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    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/41—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
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    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
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    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D493/04—Ortho-condensed systems

Abstract

Compounds useful for inhibiting HIV protease are disclosed. Methods of making the compounds, and their use as thereapeutic agents, for example, in treating wild-type HIV and of multidrug-resistant strains of HIV, also are disclosed.

Description

CARBAMATES AS HIV INHIBITORS PROTEASE FIELD OF THE INVENTION The present invention relates to compounds useful for inhibiting HIV protease enzymes. More particularly, the present invention relates to inhibitors of HIV protease, to the methods of making the inhibitors, and their use as therapeutic agents, for example, in the treatment of wild type HIV and strains resistant to multiple HIV drugs BACKGROUND OF THE INVENTION It is well known that a wide range of diseases are caused by retroviruses. As currently understood, the acquired immunodeficiency syndrome (AIDS) is a disease of the immune system caused by the retrovirus HIV (Human Immunodeficiency Virus). ) According to estimates from the World Health Organization, AIDS affects millions of people and continues to spread Virtually in all cases, AIDS causes the death of the infected individual. The retroviruses HIV-1 and HIV-2 have been identified as a cause of AIDS A retroviral protease in a proteolytic enzyme that participates in the maturation of new infectious virions in infected cells during the reproductive cycle In several retro-irus, for example, HIV-1 and HIV-2, each has a region in its genome that codes for a "gag-protease" The "gag-protease" is responsible for the correct proteolytic cleavage of precursor proteins that are produced from the genomic regions that code for the "Group-specific Antigens" (gag) The "gag-protease" cleaves the core of the p24 protein of HIV-1 and HIV-2 preferably N-thermally proline residues, for example, in the divalent residues Phe-Pro, Leu-Pro, or Tyr-Pro It is a protease having a catalytically active aspartate residue in the active center, ie, an aspartate protease During cleavage, the structural proteins of the virus core are released. The "gag-protease" itself is a component of a precursor protein encoded by the pol-genome region of HIV-1 and HIV-2, which also contain the regions for the "reverse transcriptase" and "integrase" and it is thought that it will be cleaved by means of a -pr ot eo 1 isis The retroviral protease is a decisive enzyme in the retroviral replication process The propagation of a retrovirus, such as for example, HIV , can be prevented median The exposure of the virus to a retroviral protease inhibitor. In the sense in which it is used herein, the protease inhibitor refers to compounds that inhibit the protease of viral origin, and which are useful in the prophylaxis or treatment of infections. viruses evoked by retroviruses, such as, for example, HIV, in animals, both human and non-human. Protease inhibitors perform in the final stage of viral replication, and prevent HIV from making new copies of itself by interfering with the HIV Protease Enzyme As a result, these new copies of HIV are not able to infect new cells. The retroviral protease inhibition typically involves a mimic transition state whereby the retroviral protease is exposed to a binding compound, typically from a reversible form, to the enzyme in competition with gag and gag-pol proteins to inhibit the specific processing of structural proteins and release ration of the retroviral protease itself In this way, retroviral replication proteases can be effectively inhibited. Various classes of compounds have been proposed for the inhibition of proteases, including HIV protease. These compounds include hydroxyethylamine isosteres, reduced amide isosteres, and isosteres. Non-peptidic See, for example, EP 0 346 847, EP 0 342 541, Roberts et al, "Rational Design of Peptide-Based Protein Inhibitors", Science, 248, 358 (1990), Erickson et al, "Design Activity, and 2 8 A Crystal Structure of a C2 Symmetric Inhibitor Complexed to HIV-1 Protease ", Science, 249,527 (1990), and S Tha isri vongs," S t ruct ue - Based Design of Non-Peptide HIV Protease Inhibitors ", 35th Annual Buffalo Medicinal Chemistry Meetmg, State University of New York at Buffalo, Buffalo, NY, May 1994 Also, see, for example, US Pat. Nos. 6,008,228, 6,100,277, and 6,245,806 Some antiviral compounds that act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, for example, azidothymidine or AZT WO 99/67254 contains an analysis of AIDS and HIV protease inhibitors, and is incorporated herein as a reference However, a typical problem associated with retroviral protease inhibitors, similar to HIV protease inhibitors, has been the development of inhibitor-resistant strains of virus. The present invention provides non-peptidic compounds that are effective inhibitors of the HIV protease, and are useful in the treatment of AIDS or HIV infections, including strains resistant to multiple HIV drugs SUMMARY OF THE INVENTION The present invention is directed to a novel class of quite potent HIV protease inhibitors. This class of compounds is useful in the treatment of an HIV infection. The protease inhibitors of this novel class of compounds have been synthesized and tested by its effectiveness The compounds of the present invention have a general structural formula (I) These compounds include, but are not limited to, those having the following structural components (a) compounds containing a lactam in R3, including lactams of 5, 6, and 7 members, (b) compounds containing an extension of lactam R3 via A fused ring system is sprayed, especially systems containing basic amine substituents and hydroxymethyl substituents for increased binding affinity for HIV protease, (c) compounds containing various R groups, including isobutyl, lactams, urethanes, furans, pyrans, pyrrolidines and piperidines, as well as fused ring systems oe spi roe ic 1 i co that extend from the entities mentioned above in position R2, (d) compounds that have a group R1 such as, for example, bistetrahydrofuran or a fused cyclopentyl tetrahydrofurane, as well as, other bicyclic ring systems disclosed herein. A judicious group of groups R1, R ", R3, and R'1 provides compounds which have excellent inhibitory properties including m-potency, live m-potency, and oral bi-orality. One aspect of the present invention is to provide compounds that have a structural formula (I) wherein R1 is selected from the group consisting of Ci_6alkyl, aryl, 3alkyleneheteroyl, is selected from the group consisting of Ci-6alkyl, C; -6alkynyl, C i .3a 1 qu 11 ene (Rü) .-; , heterocycloalkyl, -N H? , -NHBoc, C i _ 3 to 1 qui lenhe t e r o c e r replaced opc i ona lment e with oxo (= 0), H- (Rd) q replaced opc i ona lment e with oxo, optionally replaced with oxo, N-Boc R "is selected from the group consisting of Rd) q ?? eleven or R "1 and R3 are taken together to form either an optionally substituted aliphatic monocyclic or bicyclic ring system, or an optionally substituted macrocyclic ring system containing from twelve to twenty atoms, including one to three selected heteroatoms of oxygen, nitrogen, and sulfur, R4 is selected from the group consisting of hydro and C - -;, to 1 qu 11 enhe te roc ic 1 or to 1 qui 1 o substituted op cit on with C (= 0) aryl or C-; 3-alkylenearyl, X is selected from the group consisting of 0, NRe, S, SO, and SO; -, A and B, independently, are an aliphatic ring of five, six, or seven members , where at least one ring contains one or two of the entity X, C is an aliphatic ring of five or six members which has one to three of the entity X, and is optionally substituted with oxo, R "is an aliphatic ring of five or six members containing one to two of entity X, Rb and Rl ", independently, are selected from the group consisting of hydro, OH, C - alkyl, C: _ 3alkyleneOH, and Ci_3a 1 qu 11 eneN (Re)? r R and Rc are taken together to form an aliphatic ring of five, six, or seven members containing optionally one or two of the X entity, Rd is selected from the group consisting of Ci-4alkyl, C2 - A 1 qu in 11 o, Ci-3alquilenoCj-8het er oc i el a 1 qu 11 o, 0Re, Ci-3a 1 qui 1 enoORe, N (Re) 2, SRe, halo, nitro, CHO, cyano, NC, C (= 0) Re, OC (= 0) Re, C (= 0) ORe, C (= 0) -N (Re) 2, CH = N0H, CH = CHCH20H, N (Re) C0R% and C i -3a 1 qui 1 enN (Re) 2 fo two groups of Rd are taken together to form an aliphatic ring of five, six, or seven members that optionally contains one or two of entity X, Re is selected from the group consisting of hydro, C; -t-alkyl, C.2-ea 1 qu m 11 o, aryl, heteroaryl, C3-Scicloalkyl, THP, Ts, Boc, and C5_ shet er ocicloa lquilo, q is 0 to 3, and the salts, prodrugs or Pharmaceutically acceptable solvates thereof Another aspect of the present invention is to provide a potent HIV protease inhibitor useful in the treatment of HIV and AIDS, particularly in the treatment of wild-type HIV and HIV-resistant strains of multiple drugs. The compounds of the formula Structural (I) have shown significant activity for HIV protease inhibition Another aspect of the present invention is to provide a method of treating HIV infections in mammals using a retroviral protease inhibitor that is effective in preventing the replication of retroviruses m vitro or m vivo A protease inhibitor of the present may be used alone, or in combination with (a) a second protease inhibitor, (b) another anti-viral agent, or (c) both (a) and (b) Still another aspect of the present invention is to provide pharmaceutical compositions containing one or more compounds of the structural formula (I), for the use of the compounds and compositions containing the compounds in the therapeutic treatment of a disease or disorder , and with the methods for preparing the compounds of the structural formula (I) and the intermediates involved in the synthesis thereof. Yet another aspect of the present invention is to provide a method for inhibiting the protease of a multidrug-resistant retrovirus in a mammal infected with the retrovirus, the method comprises administering a therapeutically effective amount of one or more compounds of the structural formula (I) to the mammal to inhibit the proliferation of the retroviruses. Another aspect of the present invention is to provide a kit for the treatment of HIV. or AIDS comprising a compound of structural formula (I), or a composition n containing the same, packaged with the instructions for the administration of the compound or composition for treating HIV or AIDS Still another aspect of the present invention is to provide an article of manufacture for human pharmaceutical use, comprising (a) a container separator, (b) a container, and either (the) a packaged composition comprising a compound of the structural formula (I) and a second pharmaceutical drug or (c2) a packaged composition comprising a compound of the structural formula (I) and A packaged composition comprising a second pharmaceutical drug The second pharmaceutical drug is typically useful in the treatment of HIV or AIDS The foregoing and other aspects and advantages of the present invention are shown in the following detailed description of preferred embodiments DETAILED DESCRIPTION OF THE INVENTION PREFERRED MODALITIES Retroviral protease is a decisive enzyme in the retroviral replication process. The propagation of a retrovirus, such as for example HIV, can be prevented by exposing the virus to a retroviral protease inhibitor. The present invention is directed to the compounds of the structural formula (I), the inhibition of HIV protease, the prevention or treatment of HIV infection, and AIDS treatment In particular, the present invention is directed to compounds that treat strains resistant to multiple HIV drugs. Various protease inhibitors are currently available as a food, including saqumavir (also known as INVIRASE®, FORTOVASE®, and Ro31-8959), nelfmavir (also known as VIRACEPT®), amprenavir (also known as AGENERASE®), VX-478, and 141W94), indmavir (also known as CRIXIVAN®, L-735,524, and M-639), ritonavir (also known as NORVIR®, and ABT-538) and lopinavir (also known as ALUVIRAN® and ABT-378) All the above compounds experience an inability to treat the HIV drug-resistant strains The compounds of structural formula (I) are defined as follows (I) wherein R is selected from the group consisting of C i _ 6alkyl, aryl, C i _ 3alkyleneheteroaryl, -CH2 i Y Y R 'is selected from the group consisting Ci-6alkyl, C2-6alkynyl, C x _3a 1 qui 1 eneN (R heterocycloalkyl, - N H2, - HBoc, 3a 1 quilenhet erocycloalkyl, optionally substituted with oxo (= 0), optionally substituted with oxo, optionally substituted with oxo, is selected from the group consisting of ?? twenty-one or R "and R3 are taken together to form either an optionally substituted aliphatic monocyclic or bicyclic ring system, or an optionally substituted macrocyclic ring system containing from twelve to twenty atoms, including from one to three heteroatoms selected from oxygen, nitrogen , and sulfur, R is selected from the group consisting of hydro- and Ci -.i to the quyleneheterocycloalkyl optionally substituted with C (= 0) aryl or C i _ 3a 1 qu 11 ena r 11 o, X is selected from the group consisting of of 0, NRe, S, SO, and S0 :, A and B, ietly, are an aliphatic ring of five, six, or seven members, where at least one ring contains one or two of the entity X, C is a five or six member aliphatic ring containing one to three of entity X, and optionally substituted with oxo, Rd is a five or six member aliphatic ring containing one to two of the entity X, Rb and Rc, ietly, are selected from the group consisting of hydro, OH, Ci-ialkyl, C: _ 3alqui lenoOH, and Ci-3a 1 qu 11 eneN (Re), -:, or Rb and R ° are taken together to form an aliphatic ring of five, six, or seven members optionally containing one or two of the entity X, Rd is selected from the group consisting of Ci-4alkyl, C? -e, alkynyl, Ci_3alkyleneC] -heterocycloalkyl, 0Re, Ci -kalkylenoOR-, N (Re) -, SRe, halo, nitro, CHO, cyano , NC, C (= 0) R% OC (= 0) Re, C (= 0) ORe, C (= 0) -N (Re)?, CH = N0H, CH = CHCH £ 0H, N (Re) C0R% and C] _3alkyleneN (Re)? , or two groups of Rd are taken together to form an aliphatic ring of five, six, or seven members optionally containing one or two of the X entity, R ° is selected from the group consisting of the hydro, C2- * alkynyl, aryl, heteroaryl, C3_8cycloalkyl, THP, Ts, Boc, and C3-eheterocycloalkyl, q is 0 to 3, and the pharmaceutically acceptable salts, solvates or prodrugs thereof The present invention is also directed to pharmaceutical compositions useful for inhibiting HIV protease, the compositions comprise a compound of the structural formula (I) and a pharmaceutically acceptable carrier. These pharmaceutical compositions are useful for treating an HIV infection, or for treating AIDS or ARC. The present invention is also directed to methods of inhibiting HIV protease, methods for treating an HIV infection, and methods for treating AIDS or ARC comprising the administration of a therapeutically effective amount of a composed of the structural formula (I) or a composition containing a compound of the structural formula (I) to an individual in need thereof. In addition, the present invention is directed to a pharmaceutical composition comprising a compound of the structural formula (I). ) and an AIDS treatment agent selected from the group consisting of (a) an AIDS antiviral agent, (b) an anti-infective agent, (c) an immunomodulator, and (d) mixtures thereof The compound of the structural formula (I) and the AIDS treatment agent can be packaged separately or together, and can be administered simultaneously or sequentially. In preferred embodiments of a compound of the structural formula (I), R1 is selected from the group consisting of from -C (CH3) 3 ?? ?? Y R "is selected from the group consisting of C CH (CH:) - H, -NHBoc, - (CH.): CH-Cil /:, - (CH; H = CH:, -CH2CH2 - O ?? ?? or R and R "are taken together, with the nitrogen atom to which they are attached, to form optionally substituted with C (= 0) NHCi-galkyl, or a macrocyclic ring system containing from 16 to 20 carbon atoms, optionally including SO2, oxygen atoms, or both, and optionally substituted with one or more phenyl, benzyl, oxo (= 0) and OR ", R'1 is hydro, R" '' and R '"', independently, they are hydro or C3_3alkyl, or are taken together to form (-CH2-) 4 Y Rd is selected from the group consisting of C1-3alkyleneoOR, N (Re), Ci_3alkyl, halo, nitro, Ci-salylenoC ^ -eheterocycloalkyl, CHO, CH = OH and 0Re, or two Rd groups are taken together with the carbon atoms which are united to form As used herein, the term "alkyl" includes straight or branched chain hydrocarbon groups containing the indicated number of carbon atoms. The hydrocarbon group may contain from 1 to 20 carbon atoms, typically methyl, ethyl and straight-chain and branched propyl and butyl groups The term "alkyl", "bridging alkyl" ie a bicyclic or polycyclic hydrocarbon group Ce-ib for example, norbornyl, adamantyl, bicyclo [2 2 2] octyl, bicyclo [2 2] L-heptyl, bicyclo [3 2 l] octyl, or decahydronane The alkyl groups can be substituted, for example, with hydroxy (OH), halogen, aryl, heteroaryl, het eroc ic 1 or 1 qu 11 or , ammo (N (Re);), and sulfonyl groups (S02Re) The term "alkynyl" is similarly defined as alkyl, except that an alkyl group contains at least one carbon-carbon double bond. The term "alkylene" is defined as an alkyl group having a substituent. For example, the term "Ci-3alkyleneOH" refers to an alkyl group containing one to three carbon atoms and is replaced with a hydroxy group. The term "cycloalkyl" is defined as a group C -.- "cyclic hydrocarbon, eg, cyclopropyl, Cyclobutyl, cyclohexyl and cyclopentyl "Heterocycloalkyl" is defined only as cycloalkyl except that the ring contains one to three heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Cycloalkyl and heterocycloalkyl groups can be saturated ring systems or partially unsaturated substituted with, for example, one to three groups, independently selected from Ci- "alkyl, C x_:! a 1 qu 11 enoOH, C (= 0) NH;:, NH, oxo (= 0), aryl The term "macrocyclic" is defined as an optionally substituted ring system containing from ten to twenty atoms, optionally including up to four heteroatoms selected from oxygen, sulfur, SO-, and N (Rc). atoms present in an aryl or heteroaryl ring may contribute to the ring atoms in the crocrylic ring The term "halo" or "halogen" is defined herein to include fluorine, bromine, chlorine and iodine The term "aryl", alone or in combination, it is defined as a monocyclic or polycyclic aromatic group, preferably a monocyclic or bicyclic aromatic group, for example, phenyl or naphthyl. Unless indicated otherwise, an "aryl" group may be unsubstituted or substituted, example, with one or more, and in particular from one to four, halo, CH = NOH, Ci-6alkyl, C_ca 1 qu in 11 o, OCF3, N02, CN, NC, N (R) -, OR, C02R, C (0) N (R) 2, C (0) R, N (Ra) COR, M (Ra) C (0) OR, C: - 3alkylenoOR, and SR, wherein R is selected from the group It consists of hydro, Ci_e.alkyl, C; -alkyl, Ci or C, or I, which is substituted for l, or aryl, heteroaryl, S02Re, OTs, NHBoc, OTHP, and Ci_6alkyl substituted with halo, hydroxy, aryl, heteroaryl, hete oc oc ic 1 or 1 qu 11 o , N (Re)?., Or SO ^ R6, and R ° is as defined above Example aryl groups include phenyl, naphthyl, tet rah i drona ft i 1, chlorophenyl, methylfemlo, methoxy feni lo, trif luo rorne 111 feni 1 o, nitrophenyl, hdrox if eni 1 o, and the like The terms "ar 11 C _3a 1 qu 11 o" and "Het e roa r 11 Ci-sa 1 qu 11 o" are defined as an aryl or heteroaryl group having a substituent Ci-3a lqu i 1 o The term "heteroaryl" is defined herein as a monocyclic ring system or bicyclic containing one to two aromatic rings and containing at least one nitrogen atom, oxygen, or sulfur in an aromatic ring, and may be unsubstituted or substituted, for example, with one or more, and in particular from one to four , Substituents, for example, hydrogen, C! _alkyl, Cxalkoxy, aryl, N (Re) ¿, 0R ': and halo, where Re is as defined above Examples of heteroaryl groups include, without limitation, thienyl, furyl , pyridyl, oxazolyl, quinolyl, isoquinol, thiazolyl, triazolyl, isoquinolyl, isoxazolyl, midezolyl, benzothiazolyl, pyrazyl, pyrimidine, thiazolyl and thiazolyl. The term "hydroxy" is defined as -OH The term "Boc" is defined as t-butoxycarbonyl The term "THP" is defined as tetrahydropyranyl The term "Ts" is defined as pt or luens u 1 fo 11 oo tosyl The content of carbon atoms of the entities containing hydrocarbons is indicated by a subscript designating the minimum and maximum number of carbon atoms in the entity , for example, Ci-salkyl "refers to an alkyl group having from one to six carbon atoms, inclusive The term" Me "is methyl (CH3)," Et "is ethyl (C H., and" Ph "is phenyl (Cc-H.:,) In the structures herein, for a bond that lacks a substitute, the substituent is methyl, for example, is When no substituent attached to a carbon atom or ring is indicated, it is to be understood that the carbon atom contains the appropriate number of hydrogen atoms. Also, when no substituent attached to a carbonyl group or a nitrogen group is indicated, for example, it is understood that the substituent will be hydrogen, for example, 0 OR II II R-C is R-C-H and R-N is R-NH :: The notation And similar notations mean that the ring system is linked to the rest of the compounds via any atom of ring A or B The notation N (Rx) 2, where x represents an alpha or numeric character, such as for example, Ra, Rb , R1, R £, and the like, is used to denote two R groups attached to a common nitrogen atom. When used in this notation, the group R: '; it can be the same or different, and it is selected from the group as defined by the group R: ': The present invention is also directed to pharmaceutical compositions containing one or more compounds of structural formula (I), for use in compounds and compositions containing the compounds in the therapeutic treatment of a disease or disorder, and with methods for preparing the compounds and intermediates involved in the synthesis of the compounds of structural formula (I) In the sense in which it is used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as also, any product which results, directly or indirectly, from the combination of the specific ingredients in the specific amounts. The present invention includes all possible stereoisomers and geometric isomers of the compounds of the structural formula (I). The present invention includes only racemic compounds but also the isomers Optically active compounds When a compound of the structural formula (I) is defined as an individual enantiomer, this can be obtained either by resolution of the final product or by static stereo synthesis from either an isomerically starting material. pure or the use of a chiral auxiliary reagent, for example, see Z Ma et al, Tetrahedron Asymmetry, 8 (6), pages 883-888 (1997) The resolution of the final product, an intermediate, or a starting material can be achieved by any suitable method known in the art Adi conally, in situations where tautomers of the compounds of the structural formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds. As demonstrated hereinafter, specific stereoisomers may exhibit an exceptional ability to inhibit HIV protease. , and may be used alone or in combination with other HIV and AIDS therapies. As used herein, the term "pharmaceutically acceptable salts" refers to the compounds of structural formula (I) that contain acidic and form salts with suitable cations Suitable pharmaceutically acceptable cations include alkali metal cations (eg, sodium or potassium) and alkaline earth metal (eg, calcium or magnesium) The pharmaceutically acceptable salts of the compounds of structural formula (I), containing a basic center, are acid addition salts formed with pharmaceutical acids. acceptable Examples include the salts of hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or acid phosphate, acetate, benzoate, succmate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, and p-toluensulphonate. In light of the foregoing, any reference to the compounds of the present invention appearing herein is meant to include the compounds of the structural formula (I), as well as the pharmaceutically acceptable salts, prodrugs and solvates thereof The term "prof armaco", in the sense in which it is used herein, refers to compounds that rapidly transform m to compounds having the structural formula (I), for example, by hydrolysis. The design of the prodrug is discusses generally in Hardma et al (Eds), Goodman and Gilman's The Pha rmaco logi ca 1 Basis of Therapeutics, 9th ed, pp 11-16 (1996) A full analysis is provided in Higuchi et al, Pr odrugs as Novel Delivery Systems, Vol 14, ASCD Symposium Series, and Roche (ed), Bioreversible Ca rriers m Drug Design, American P armaceutical Association and Pergamon Press (1987) Typically, the administration of a drug is followed by elimination of the body or some biotransformation by which the biological activity of the drug is reduced or eliminated. Alternatively, a biotransformation process can lead to a metabolic by-product, which in itself is more or equally active compared to the drug administered initially. The increased understanding of these biotransformation processes allows the design of the so-called "prodrugs", which, after biotransformation, are more physiologically active in their altered state. Therefore, the prodrugs encompass compounds that are converted to pharmacologically active metabolites. , the prodrugs can be converted into a pharmacologically active form to tr prior to the hydrolysis of, for example, an ester or amide bond, by introducing or exposing a functional group of the resulting product. The prodrugs can be designed to react with an endogenous compound to form a water-soluble conjugate that also improves the pharmacological properties of the compound, for example, increased circulatory half-life Alternatively, the prodrugs can be designed to undergo a covalent modification on a functional group with, for example, glucuronic acid, sulfate, glutathione, an amino acid, or acetate The resulting conjugate it can be activated and excreted in the urine, or it can be made more potent than the original compound High molecular weight conjugates can also be excreted in the bile, can be subjected to enzymatic cleavage, and can be released back into the circulation, increasing 'effectively with this the biological half-life of the compound originally administered The present invention can be added therapeutically as the pure chemicalalthough it is preferred to administer the compounds of structural formula (I) as a pharmaceutical composition or formulation Accordingly, the present invention also provides pharmaceutical formulations comprising a compound of structural formula (I), or pharmaceutically acceptable salts thereof. , together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and / or prophylactic ingredients. The carriers are "acceptable" in the sense that they are compatible with the other ingredients of the formulation and do not harm the recipient thereof. HIV protease is typically measured using a dose-response analysis in which a sensitive analysis system is contacted with a compound of interest on a variation of concentrations at which no effect is observed or minimal effects are observed, up to higher concentrations in which some pair effect is observed This curve can be described as a curve that expresses a degree of inhibition as a function of the concentration. The curve theoretically passes to through a point at which the concentration is sufficient to reduce the activity of the HIV protease enzyme to a level that is 50% that of the difference between the minimum and maximum enzyme activity in the analysis. This concentration is defined as the Inhibitory Concentration. (50%) or IC50 Comparisons of the efficacy of the inhibitors are often given with reference to the comparative IC50 values, where a higher ICS.0 value indicates that the compound is less potent, and an IC a value indicates that the compound is more potent than a reference compound. The compounds useful for the method of the present invention demonstrate an IC¾ value of less than 100 μ? when measured using the dose response analysis Preferred compounds demonstrate an IC = value, less than 50 μ? The most preferred compounds demonstrate an IC5 value: j less than 5 μ? Even more preferred compounds for the present invention demonstrate an ICf value. less than 3 μ? (3000 M), less than 0 5 μ? (500 NM), and less than 0 1 μ? (100 NM), for example, 5 μ? for 0 1 NM Compounds and pharmaceutical compositions suitable for use in the present invention include those in which the active ingredient is administered in an effective amount to achieve its intended purpose More specifically, a "therapeutically effective amount" means an amount effective to inhibit the development of, or to alleviate the existing symptoms of, the subject to be treated The determination of the effective amount is within the ability of those skilled in the art, especially in light of the detailed description provided herein A "dose" "Therapeutically effective" refers to that amount of the compound that results in the desired effect being achieved. The toxicity and therapeutic efficacy of these compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine LD50 (the lethal dose to 50% of the population) and the ED 5;, (the therapeutically effective dose in 50% of the population) The dose ratio between toxic and therapeutic effects is the therapeutic index, which is expressed as the proportion of L D5 or ED50. Compounds that exhibit high therapeutic indices are preferred. (ie, a toxic dose that is substantially greater than the effective dose) The obtained data can be used to formulate a range of dosages for use in humans The dosage of these compounds preferably depends on a range of circulating concentrations that include ED53 with little or no toxicity Dosage may vary within this range depending on the dosage form used, and the route of administration used The term "container" indicates any receptacle and closure therefore suitable for storage, transport, distribution and / or handling of a pharmaceutical product The term "separate" means the information that accompanies to a product that provides a description of how to administer the product, together with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding the use of the product. The container separator in general it is referred to as the "label" for a pharmaceutical product. The exact formulation, route of administration, and dosage can be selected by the individual physician in view of the patient's condition. The dosage amount and range can be individually adjusted to provide plasma levels of the active entity that is sufficient to maintain the therapeutic effects The pharmaceutical compositions of the invention can be formulated to include a compound of the structural formula (I) and one or more additional agents useful in the treatment of HIV and AIDS. For example, the compounds of the present invention can be effectively administered to a p pre-exposure and / or post-exposure period, in combination with a therapeutically effective amount of an AIDS antiviral, immunomodulatory, anti-mfective, or vaccine, such as for example those described in U.S. Patent No. 6,245,806, incorporated herein by reference As will be appreciated by those skilled in the art, reference is made herein to a treatment extending to prophylaxis, as well as to a treatment or established diseases or symptoms. It will be further appreciated that the The amount of a compound of the invention required to be used in the treatment varies with the nature of the condition to be treated, and with the age and condition of the patient, and ultimately determined by the attending physician or veterinarian. In general, the dosages used for adult human treatment are typically in the range of O 001 mg / kg to approximately 100 mg / kg per day Dosage The desired dose can be administered in a single dose, or as multiple doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. In practice, the physician determines the actual dosage regimen that is most suitable for an individual patient, and the dosage varies with the age, weight and response of the particular patient. The above dosages are examples of the average case, although there may be individual cases in which higher or lower dosages are warranted, and are within the scope of the present invention The terms "administration of" and "administering" a compound should be understood as the provision of a compound of the invention or a prodrug of a compound of the invention to an individual in need of treatment. Thus, in accordance with important features of the present invention, a method of treatment, and a pharmaceutical composition for the treatment of HIV infection and AIDS Treatment involves administering to a patient in need of this treatment a pharmaceutical composition comprising a pharmaceutical carrier, a therapeutically effective amount of a compound of the structural formula (I), and an optional agent useful in the treatment of HIV or AIDS The compounds and compositions of the present invention can be administered in a standard manner for the treatment of indicated diseases, such as, for example, oral, parenteral, transmucosal (eg example, sub-1 ingual lmen teo via oral administration), topical, transdermal, r ectally, via inhalation (eg, nasal or deep inhalation of the lung) Parenteral administration includes, inter alia, intra-arterial, intra-arterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, and intra-articular administration. parenteral can also be carried out using a high pressure technique, similar to POWDERJECTMR. These preparations can also be formulated as suppositories, for example, containing conventional suppository bases, such as, for example, cocoa butter or other glycerides. Inhalation can typically be provided in the form of a solution, suspension, or emulsion that can be administered as a dry powder, or in the form of an aerosol using a conventional propellant, such as, for example, dichlorodifluoromethane or trichloroforomethane. Topical formulations and typical transdermals comprise conventional aqueous or non-aqueous vehicles, such as for example, eye drops, creams, ointments, lotions and pastes, or are in the form of a medicated patch, patch or membrane. Additionally, the compositions of the present invention can be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents, such as, for example, suspending, stabilizing, and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (eg, pyrogen-free, sterile water) before being used. A composition of the present invention can also be formulated as a depot preparation. These long-acting formulations can be administered by implantation ( for example, subcutaneously or muscularly) or by in Intramuscular Election Accordingly, the compounds of the present invention may be formulated with suitable polymeric or hydrophobic materials (eg, an emulsion in an acceptable oil), ion exchange reams, or as a sparingly soluble derivative (e.g., a salt poorly soluble) For veterinary use, a compound of formula (I), or a non-toxic salt thereof, is administered as a suitably acceptable formulation in accordance with normal veterinary practice. The veterinarian can easily determine the dosage regimen and route of administration. administration that is most suitable for an animal for which the r As set forth above, the HIV protease inhibitors of the present invention can be administered as the sole active agent, or they can be used in combination with a second active agent that is effective against retro-viruses, such as, for example, HIV-1 These second active agents include, in an Other HIV protease inhibitors, various nucleoside analogues, nucleoside reverse transcriptase inhibitors, ant i -vi rals, immunomodulators, anti-infectives, tat antagonists, and glucosidase inhibitors Many examples of these second active agents are shown in U.S. Patent Nos. 6,100,277 and 6,245,806, both incorporated herein by reference, and include, without limitation Ro 31-859, KNI-272, AZT, DDI, DDC, 3 TC, D4T, PMEA, Ro 5-3335, Ro 24-7429, mdinavir, ritonavir, saquinavir, nelfmavir, amprenavir, abacavir, castanosine, castanospermine 6-but ri-lester, N-butyl-1-deoxynojirimycin, N-butyl-l-deoxino] -inmycin per-butrilester, 097, acemannan, acyclovir, AD-439, AD- 519, adefovir clipivoxil AL-721, alpha inferno, ansamycin, beta-f luoro-ddA, BMS-232623, BMS-234475, CI-1012, cidofovir, of 1 airi di na, EL-10, efaviren, f ame ic 1 ovi r, FTC, hypericma, Compound Q, ISIS 2922, lobucavir, nevirapma, novaprene, T peptide, octapeptide, PNU-140690, probacol, stavudine, valac iclovir, virazole, zalcitabine, ABT-378, biririmma, gamma inferione, interleukin-2, TNF, etanercept, mfliximab, fluconalzole, piritrexim, trimetrexate, daunorubicma, leukotriene B4 receptor antagonist and analogue and prodrugs thereof Protease inhibitors of the present invention and the second active agent can be formulated as separate compositions that are administered practically at the same time, i.e., simultaneously or sequentially, or the therapeutic agents can be administered from a single composition, such that all the active agents are present in the host in a therapeutically effective amount. Alternatively, the therapeutic agents can be administered to the host at different times, ie, separately, such that only one of the two active agents at a time are present in the host. the host in a therapeutically effective amount The compounds of the structural formula (I) are effective antiviral compounds and, in particular, are effective retroviral inhibitors. In this way, the compounds of the present invention are effective HIV protease inhibitors. The compounds of the present invention also inhibit other retroviruses, such as, for example, lentivirus, in particular, other strains. of HIV, for example HIV-2, human T-cell leukemia virus, sarcoma rous virus, simian immunodeficiency virus, feline leukemia virus, feline immunodeficiency virus, and the like The compounds of the structural formula ( I), therefore, are effective in the treatment and / or prophylaxis of retroviral infections. In addition, the compounds of the structural formula (I) are effective in preventing the growth of retroviruses in a solution. Both human and animal cell cultures, such as such as, for example, T lymphocyte cultures, are used for a variety of purposes, such as, for example, the investigation and diagnosis of procedures that include calibrators and controls. Before and during the growth and storage of a cell culture, the inhibitors herein can be added to a cell culture medium, the inhibitors herein can be added to a cell culture medium at an effective concentration for avoid the unexpected or unwanted replication of a retrovirus that may be present inadvertently or unknowingly in cell culture. For example, viruses may be present in the cell culture originally because HIV is known to be present in lymphatic human T-waves for prolonged periods before blood can be detected, or through exposure to the virus This use of the present inhibitors avoids the unwitting or inadvertent exposure of a potentially lethal retrovirus to a researcher or mediator. , therefore, provides a pharmaceutical composition comprising a compound of the structural formula (I), together with a pharmaceutically acceptable diluent or carrier thereof The present invention also provides a process for preparing a pharmaceutical composition comprising mixing a compound of the formula (I), together with a pharmaceutically acceptable diluent or carrier thereof. In addition, articles of manufacture are provided which comprise a compound of structural formula (I) and a second pharmaceutical drug, packaged separately or together, and a separator having instructions for use the active agents The specific non-limiting examples of the compounds of the formula structure (I) are given below, the syntheses thereof being carried out according to the procedures shown hereinafter Example 1 Example 2 Example 10 H O 60 Example 14 14a R = Me (methyl) 14b R = Et (ethyl) Example 15 15a Y = OH 15b Y = NHMe Example 16 16a Z = OH 16b Z = CH 2 OMe In general, the compounds of structural formula (I) can be prepared according to the synthetic schemes depicted herein. In these synthetic schemes, it is understood in the art that protecting groups can be employed when necessary in accordance with the general principles of synthetic chemistry These protecting groups are removed in the final steps of the synthesis under basic acidic or hydrogenolourous conditions which are readily apparent to those skilled in the art When employing adequate handling and protection of the chemical functional groups, the synthesis of the compounds of the structural formula (I) not specifically shown here can be carried out by analogous methods to the scheme shown in the present invention. The compounds of the present invention were tested for their ability to inhibit HIV-1 protease by the test method shown below The d The following examples show that the compounds of the present invention are potent inhibitors of HIV protease. Analysis for inhibition of HIV-1 protease The HIV-1 protease gene was subcloned into the vector pET30a (Novagen ) and then transformed into BL21 (dE3) pLysS cells for protein expression Protein expression and purification were followed according to the Tang procedure (Hong et al, Biochemistry, 1996, 35, 10627-10633) The accumulation of proteins resulted in cell inclusion bodies Cell lysates analyzed by SDS pol i ac ri 1 amide gel electrophoresis showed the expected major band 11 kDa The inclusion body containing some bacterial proteins was washed completely when using TRITON X- 100, solubilized in 8M urea and passed through a Q-sepharose column to remove the bacterial proteins that interfered with the refolding steps Subsequent HIV-1 protease was refolded from urea to an active form by dialysis. As a final step, gel filtration chromatography was used to remove impurities after refolding. The activities of the purified HIV-1 protease were examined using a substrate f luorogeni co, 2-ammobenzoyl-Thr-Ile-Nle-Phe (pN02) -Gln-Arg-NH2 (Novabiochem) Kinetic measurements of the cleavage of the anthranilyl fluorogenic substrate by the HIV-1 protease showed a Michaelis behavior -Menten typical The Michaelis constant for the substrate is Kra = 4 5 μ? Using the first derivative equation, we calculate kcat In the condition of S0 < < Kr., V = E0 (kcat Km) Sc, where E0 is the total enzymatic concentration, and S0 is the substrate concentrate Then, kt = 0 70 ± 0 05 s "1 The analyzes were carried out as described by Toth and Marshal (Toth et al, Int J Pept Protem Res, 1990, 36, 544-50) EXPERIMENTATIONS (3aR, 5R, 6aR) - (2 'r5' -dioxo-pyrrolidin-1-yl-ester) - hexahydrocyclopenta [b] furan-5-yl ester of carbonic acid (4) Cyclopentadiene f, g, n OTB E pplication (a) Tíourea, Rose Bengal, 0. |, MeOH, hv, 8h, (b) Ac? 0, Py, DMAP, CH;: C12, 1 hour 42 * during two steps, (c) NaN3, acetylcholinesterase (type Vl-S) phosphonate buffer (0 5 M, pH 7 0), 12 hours, 70%, (d) TBSC1, imidazole, DMF, 30 minutes, (e) K CO 3, MeOH, 20 minutes 94 last Two steps, (f) NBS, ethyl vinyl ether, - 450 C at 23 ° C, 12 hours, (g) n - Bu 3 S n H, AIBN, benzene, reflux, 4 hours, (h) BF · OEt -, Et-¾SiH, CH2Cl.- :, 0 ° C, 10 minutes, (1) 45% aqueous HF, CH5CN, 15 minutes, (j) DSC, EtiN, CH3CN, 2 hours, 47 * during two steps A solution f of c 1 c 1 ope ntad 1 ene (16 mL), thiourea (10 g), and Rose Benqal (300 rr.q) in methanol (MeOH) (1000 mL) was purged with oxygen and irradiated with a Halogen of 75 Watts After 8 hours, the solution was kept at room temperature in the absence of light for 12 hours. The solvents were eroded under reduced pressure, then MeOH (200 mL) was added. After filtering, the The mixture was concentrated and the crude product was passed through a column of silica gel to provide a crude diol. The diol was used, acetic anhydride (AC: >).; 0) (58 8 g, 0 57 mol), p indina (77 g, 1 15 mol) and DMAP (4-d íme 111 ammop 1 r 1 di na) (200 mg) in methylene chloride (CH2Cl2) ( 1000 mL) were stirred for 2 hours The reaction mixture was washed with water (2 x 300 mL) then concentrated The resulting crude diacetate was purified by chromatography on silica gel to obtain 17 9 g (42%, two steps) of the H NMR diacetate (CDC13, 00 MHz) d 6 07 (m, 2H), 5 5 (m, 2H) r 2 85 (m, 1H), 2 05 (s, 6H), 1 7 (m, 1H) The diacetate (4 1 g, 22 8 mmol), sodium azide (N aN | ¾) (15 mg), and acetyl cholinesterase (2 8 mg, type VI-S, from Electric Eel, Sigma, Inc) were slowly stirred in phosphate buffer (0 5 M, pH 7 0) for 12 hours. Then, the reaction mixture was extracted with EtOAc (EtOAcj (3 x 200 mL), washed with brine (200 mL), and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel to obtain 2 2 g (70%) of compound 1, [a] - '+59 35 (89% ee) (IR, S) -4- (tert-butyl-dimethylsilanyloxy) -cyclopent-2-enol (2) Alcohol (200 mg, 48 mmol), tert-butyldimethylsilanyl chloride (TBSC1) (267 mg, 488 mmol) ), and imidazole (191 mg, 2 86 mmol) in dimetre 11 f ormamide (DF) (10 mL) were stirred for 30 minutes. Then, the reaction mixture was diluted with EtOAc (50 mL) and washed several times with water (2 x 50 mL) The organic layer was dried over anhydrous sodium sulfate (a2S04) and the solvents were evaporated m vacuo Purification of the crude product by chromatography on silica gel provided the ether TBS as a colorless liquid TBS ether and Potassium carbonate (K2C03) (323 mg, 34 mmol) in MeOH (10 mL) was stirred for 20 minutes at room temperature The MeOH was evaporated and the reaction mixture was extracted with EtOAc (2 x 50 mL), dried on a2SO ^ anhydrous, and concentrated under reduced pressure. Silica gel chromatographic purification of the crude product yielded compound 2 (300 mg, 94%, two steps). as a colorless oil 'NMR (CDC13 / 200 MHz) 6 5 92 (m, 2H), 4 6 (m, 2H), 2 68 (m, 1H), 1 77 (m, 1H), 1 49 (m, 1H), 0 90 (s, 9H), 0 09 (s, 6H) (3aR, 5R, 6aR) -5-tert-butyldimethylsiloxy-hexahydrocyclopenta [b] furan (3) A solution of compound 2 (300 mg, 1 4 mmol) and N-bromosuccimide (NBS) (248 mg, 1 4 mmol) in CH2Cl2 (5 mL) at -45 ° C was added to ethyl vinyl ether (151 mg, 2.1 mmol) The resulting mixture was warmed to room temperature and, after 12 hours, treated with aqueous ammonium chloride (NH C1) ( 10 mL], then washed with brine (50 mL). The organic layer was dried over anhydrous Na2SC, then concentrated to vacuo. Purification of the crude product by chromatography on silica gel provided a bromoethoxy compound (468 mg) as a colorless liquid. The bromoethoxy compound (464 mg, 11 mmol), t 1 -n-but 11 t 1 n hydride (nBu3SnH) (412 mg, 41 mmol), and AIBN (10 mg) in benzene (5 mL) were added. refluxed for 4 hours The reaction mixture was then cooled to room temperature, and the crude product was subjected to silica gel chromatography to obtain a bicyclic ether (300 mg) as a viscous liquid To the bicyclic ether ytr 1 et 11 s 11 ano (EtiSiH) (331 mg, 2.85 mmol) in CH2CI2 (5 mL) at 00 C was added tr 1 f 1 boron oxide solution (BF. ^ OEt.-) (2 85 mmol) The reaction was completed in 10 minutes. Sodium bicarbonate (NaHCC > 3) (10 mL) and the reaction mixture was extracted with CH2Cl2 (2 x 10 mL). The combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by chromatography on silica gel provided compound 3 as a colorless liquid. 1 H NMR (CDC13, 400 MHz) d 4 39 (m, 1 H), 4 06 (m, 1 H), 3 88 (m, 1 H), 3 78 (m, 1 H j, 2 53 (m, 1 H), 2 1-1 9 (m, 3H), 1 72 (m, 1H), 1 58 (m, 1H), 1 42 (m, 1H), 0 91 (s, 9H), 0 03 (s, 6H) (3aR, 5R, 6aR) - (-2 ', 5'-dioxo-pyrrolidin-1-yl ester of carbonic acid) -hexahydro-cyclopenta [b] furan-5-llester (4) Ether 3 was stirred (175 mg , 0 72 mmol), HF (45%, 0 2 mL), and CHjC (2 mL) in a plastic container for 15 minutes. NaHCO;, aqueous (5 mL) was added to the mixture and the contents of the flask were extracted. with EtOAc The combined organic layer was washed with brine (10 mL) to obtain the crude alcohol which was purified by chromatography on silica gel [a] 25D -1467 °, c, 1 85, CHC13: H NMR (CDCl;, , 200 MHz) d 4 36 (dt, 1 H, J = 1 43 Hz, 6 4 Hz), 4 22 (m, 1 H), 3 98 (m, 1 H), 3 58 (m, 1 H), 2 71 ( mr 1H), 2 5 (s, 1H), 2 2-1 5 (m, 6H) The above alcohol (73 mg, 609 mmol), carbonate, β-disuccimidyl (187 mg, 0 731 mmol), and triethylamine (Et-j) (92 mg, 0 913 mmol) in CH3CN (2 mL) was stirred for 12 hours. The solvents were evaporated and the crude alcohol was purified by chromatography on silica gel to provide carbonate 4 (91 mg,47%, two steps) < 3aS, 5S, 6aS) - (2 ', 5'-dioxo-pyrrolidin-1-ylster carbonic acid) -hexahydrocyclopenta [b] furan-ester (6) Explanation (a) NBS, et 11 vini leter, -45 ° C to 23 ° C, 12 hours, (b) n-Bu3SnH, AIBN, benzene, reflux, 4 hours, (c) BF3 0Et;:, Et3SiH, CH2Clr , 0 ° C, 10 minutes, 58% during three steps, (d) K2C03, MeOH, 90 minutes, and (j) DSC, Et3N, CH3CN, 12 hours, 92% during two steps (3aS, 5S, 6aS) -hexahydrocyclopenta [b] -furan-5-ylster of acetic acid (5) To alcohol 1 (199 mg, 1 4 mmol) and N-bromosuccinimide (249 mg, 1 4 mmol) in CH 2 Cl 2 ( 5 mL) at -45 ° C was added 111 vini 1 et er (152 mg, 11 mmol) using the same reaction conditions as in the synthesis of compound 3 to obtain a bromine compound (332 mg) H NMR (CDC15 , 200 MHz) d 6 0 (m, 2 H), 5 5 (m, 1 H), 4 7 (m, 2 H), 3 6 (m, 2 H), 3 35 (d, 2 H, J = 5 3 Hz) , 2 8 (m, 1H), 2 0 (s, 3H), 1 8 (m, 1H), 1 2 (t, 3H, J = 7 Hz) The bromine compound (332 mg, 13 mmol), nBu3SnH (395 mg, 1 35 mmol), and 2, 2'-azobisiso-butyronitrile (AIBN) (20 mg) in toluene were brought to reflux as described in the synthesis of compound 3 to obtain a bicyclic ether (228 mg) as a colorless oil To the bicyclic ether (228 mg, 1065 mmol) and Et3SiH (370 mg, 3 196 mmol) in CH C12 (5 mL) at room temperature, BF3 »OEtv (450 mg, 3 196 mmol) was added following the same reaction conditions as the d written in the synthesis of compound 3 to obtain compound 5 (140 mg, 58% three steps) as an XH NMR oil (CDC13, 200 MHz) 8 5 (m, 1H), 4 5 (m, 1H), 3 95 (m, 1H), 3 74 (m, 1H), 2 7 (m, 1H), 2 1 (m, 3H), 2 ( s, 3H), 1 5-1 9 (m, 3H) (3aS, 5S, 6aS) - (2 ', 5'-dioxo-pyrrolidxn-l-ilester of carbonic acid) -hexahydrocyclopenta [b] furan-5-ylstei (6) Compound 5 (133 mg, 0.78 mmol) and K2C03 (215 mg, 1 56 mmol) in MeOH (5 mL) was stirred for 1.5 hours. The reaction mixture was then diluted with EtOAc (20 mL) and washed several times with water. The organic layer was dried over Na2. SC anhydrous and concentrated at or reduced pressure at 30 ° C to obtain a volatile alcohol [] 25D +8 6, c, 0 7, CHC13 Alcohol, carbonate of?,? '- di s ucc i nimidi 1 o (240 mg 0.988 mmol), and Et3N (157 mg, 56 mmol) in acetonitrile (5 mL) were stirred for 12 hours. Then, the reaction mixture was diluted with EtOAc (20 mL), and washed with brine (20 mL). ) The organic layer was dried over Na;: SO, j anhydrous and concentrated under reduced pressure. The crude product was purified by a silica gel column to obtain compound 6 (195 mg, 92%, two steps) as an oil: H NMR (CDC13, 300 MHz) d 5 1 (m, 1 H), 4 48 (m, 1 H), 3 95 (m, 1 H) , 2 0-2 3 (m, 4H), 1 8 (m, 2H) Synthesis of 4-hydroxy-3-methylbenzoic acid (8) 7 8 Explanation a) NaN02, H2S04, H20, -5 ° C, reflux 2,5-dioxo-pyrrolidin-1-ylster hexahydro-furo [2,3-b] furan-3-ylster of carbonic acid (15) and (16) 15 Explanation (a) N-Yodosucmimide, propargyl alcohol, CH2C12, 0-23 ° C, 2 hours, 92%, (b) Cobaloxime (cat), NaBH4, EtOH, 50 ° C, 2 hours, 73% or Bu3SnH, AIBN, toluene, reflux, 1 hour, 76%, (c) 03, CH2C12 MeOH, 30 minutes, Me2S, -78 0 ° C to 23 ° C, 30 minutes, (d) NaBH4, EtOH, 0 ° C, 2 hours, 75%, (e) immobilized lipase 30, Arc20, DME, 23 ° C, 42%, (f) DSC, E13, CH3CN, 24 hours, 75%, (q) K2C03, MeOH, 1 hour (h) DSC, Et3N, CH3C, 1 hour, 73% during two steps Trans-2- (propargyloxy) -3-iodo-tetrahydrofuran (10) To a stirred, ice-cooled suspension of 15 g (66.6 mmol) of -siluccinimide in 150 mL of CH2C12 was added a mixture of dihydrofurane (66.6 mmol, 4 67 g, 5 1 mL) and propargyl alcohol (100 mmol, 5 0 g, 5 2 mL) in 50 mL of CH? C12 over 20 minutes After heating to 24 ° C with stirring for 2 hours, 200 mL were added of water and continued stirring for 1 hour The layers were separated and the aqueous layer was brought with 2 x 100 mL of CH2C12 The combined organic extracts were washed with a brine solution containing a small amount of sodium thiosulfate (N a i-S20 j) (70 mg), dried over N a? S0. Anhydrous, filtered, and concentrated. Chromatography on silica gel using 30% EtOAc in hexane provided (15.4 g, 92%) of iodoeter 10 as a 1H-NMR (CDC13) d 5 4 oil ( br s, 1H), 4 0-4 3 (m, 5H), 2 7 (m, 1H), 2 48 (br s, 1H), 2 25 (m, 1H), IR (pure), 2956, 2180 , 1621, 1440 cnT1 (3aR, 6aS) and (3aS, 6aR) -3-methylene-4H-hexahydro-uro [2, 3-b] furan (11) (tnbutyltin hydride procedure) To a reflux solution of tributyl hydride (20 7 mL, 77 mmol) containing AIBN (100 mg) in toluene (200 mL) was added a solution of 15.4 g (61 mmol) of iodotetrahydrofuran 10 in toluene (50 mL) dropwise over a period of one hour The resulting mixture was stirred at reflux for an additional 4 hours (monitored by TLC) The mixture was then cooled at 23 ° C and concentrated under reduced pressure. The residue was partitioned between petroleoether and acetonitrile (200 mL of each), and the acetomtril layer (lower) was concentrated. The residue was purified by chromatography on silica gel, using 10% of EtOAc in hexane as the eluent to give the product 11 (5 84 g, 76%) as a 1 H-NMR (CDC13) 6 5 7 oil (d, 1H, J = 4 9 Hz), 4 9-5 1 ( m, 2H), 4 3-4 6 (m, 2H), 3 7-4 O (m, 2H), 3 3 (m, 1H), 1 8-2 2 (m, 2H), IR (pure) , 2970,1645, 1430 cm "1 (3aR, 6aS) and (3aS, 6aR) -3-methylene-4H-hexahydro-furo [2, 3-b] furan (11) (catalytic cobaloxime process) To a solution of iodine-10 (6 4 g, 4 mmol) in 95% ethanol (80 mL) was added solid sodium borohydride (NaBH4) (1 06 g, 28 mmol) and 10 N sodium hydroxide (NaOH) (26 mL, 26 mmol) The solution was washed abundantly with N2 and several portions of finely powdered cobaloxime (611 mg, 1 5 mmol) were added over a period of one hour at 50 ° C (bath temperature 65 ° C). The resulting mixture was stirred for an additional hour, then the The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with brine and the mixture was completely extracted with ether (3 x 150 mL). The combined organic layers were washed with water, then brine, and dried over Na: SO-anhydrous Evaporation of the solvent gave a residue which was subjected to chromatography on silica gel to give the product 11 (2.3 g, 73%) as a ceite 1H-NMR (CDC13) d 5 7 (d, 1H, J = 4 9 Hz), 4 9-5 1 (m, 2H), 4 3-4 6 (m, 2H), 3 7-4 O ( m, 2H), 3 3 (m, 1H), 1 8-2 2 (m, 2H), IR (pure) 2970, 1645, 1430 cm "1, MS (70 eV) m / z 126 (m +) (3S, 3aR, 6aS) and (3R, 3aS, 6aR) -3-hydroxy-4H-hexahydrofuro [2, 3-b] furan (12) An ozone stream was dispersed over a solution of compound 11 (5 84 g) , 46 4 mmol) in MeOH (150 mL) and CH2C1- (150 mL) at -78 ° C for 30 minutes The resulting blue solution was purged with nitrogen until it faded, then quenched with 20 mL of dimethyl sulfide The resulting mixture was allowed to warm to 23 ° C. The mixture was then concentrated under reduced pressure to provide a crude ketone. The ketone was dissolved in ethanol (50 mL), cooled to 0 ° C, and sodium borohydride was added ( 2 1 g, 55 6 mmol) The reaction mixture was stirred for a further 2 hours at 0 ° C, and then quenched with 10% aqueous citric acid (10 mL). The resulting mixture was concentrated under reduced pressure, and the The residue was partitioned between EtOAc and brine. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SC > 4 anhydrous and concentrated carefully under reduced pressure. The resulting residue was chromatographed on silica gel using 30% EtOAc in hexane as the eluent to give (4 52 g, 75%) racemic alcohol 12 as a 1 H-NMR oil. (CDC13) 6 5 7 (d, J = 5 13, 1H), 4 45. { dd, J = 6 8, 14 6, 1H), 3 9-4 0 (m, 3H), 3 65 (dd, 1H, J = 7, 9 1), 2 9 (m, 1H), 2 3 ( m, 1H), 1 85 (m, 2H), IR (pure) 2951, 1640, 1346, 1210 cm "1, MS (70 eV) m / z 131 (m ++ H) Preparation of immobilized amano lipase 30 Commercially available celite 521 (4 g, Aldrich) was loaded in a Buchner funnel and washed successively with 50 mL of desiomated water and 50 mL of 0 05 N phosphate buffer (pH = 7 0, Fisher Scientific) The washed celite was then added to a suspension of 1 g of the amano lipase 30 in 20 mL of phosphate buffer 0 05 N The resulting suspension was dispersed in a glass dish and allowed to air dry at 23 ° C during 48 hours (weight 5 4 g, water content of approximately 2% by the Fisher method) (3R, 3aS, 6aR) -3-hydroxyhexahydrofuro [2, 3-b] furan (13) by acylation catalyzed by immobilized lipase A stirred solution of racemic alcohol 12 (2 g, 15.4 mmol) and Ac20 (4 g, 42 4 mmol) in 100 mL of DME (dimethylether of e 111 eng 1 ico 1) was added 2 7 g (approximately 25% by weight) of the lipase, PS30) of the immobilized amantase lipase and the resulting suspension was stirred at 23 ° C. The reaction was monitored by TLC and LH NMR analysis until a conversion of 50 was achieved; The reaction mixture was filtered, and the filter cake was repeatedly washed with EtOAc The combined filtrate was carefully concentrated on a rotary evaporator, keeping the temperature bath below 15 ° C. The residue was subjected to chromatography on silica gel for provide 843 mg (42%) of compound 13 (95% ee, [a] 2- :, -11 9o, c 1 24, MeOH), 1 H-NMR (CDC13) 6 5 7 (d, 1H, J = 5 1 Hz), 4 45 (dd, 1H, J = 6 8, 14 6 Hz), 3 85-4 0 (m, 3H), 3 65 (dd, 1H, J = 7 0, 9 1 Hz), 2 9 (m, 1H), 2 3 (m, 1H ), 1 85 (, 2H), too, 1 21 g of compound 14 after washing with 5% aqueous sodium carbonate (45%, [a] 25D +31 8o, c186, MeOH), 1H- NMR (CDC13) 8 5 7 (d, 1H, J = 5 2 Hz), 5 2 (dd, 1H, J = 6 4, 14 5 Hz), 3 8-4 1 (m, 3H), 3 75 ( dd, 1H, J = 6 6, 9 2 Hz), 3 1 (m, 1H), 2 1 (s, 3H), 1 85-2 1 (m, 2H), IR (pure) 2947, 1750, 1630 , 1338, 1220 cm ": (3S, 3aS, 6aR) -2,5-dioxo-pyrrolidin-1-ylster hexahydrofuro [2, 3-b] furan-3-ylster of carbonic acid (15) Compound 13 (2 g, 15 3 mitiol), N, N'-di-succmimidi carbonate (476 g, 18.5 mmol), and triethylamine (Et: N) (412 g, 40 mmol) in acetonitrile (CH3CN) (50 mL) were stirred for 24 hours. The reaction mixture was then diluted with EtOAc (100 mL), washed several times with brine, then dried over N to anhydrous SO4 and concentrated under reduced pressure to provide crude compound 15, which was purified by column chromatography to obtain active carbonate. 3 1 g, 75%), mp 128-130 ° C LH NMR (CDC 13, 200 MHz) d 5 74 (d, 1H, J = 5 1 Hz), 5 26 (m, 1H), 4 (m, 4H), 3 1 (m, 1H), 2 84 (s, 4H), 1 88-2 2 (m, 2H) (3S, 3aS, 6aR) -2,5-dioxo-pyrrolidin-1-ylster hexahydrofuro [2, 3-b] furan-3-ylster of carbonic acid (16 Compound 14 (500 mg, 2.9 mmol) and KCO3 (802 mg, 5 mmol) in MeOH (25 mL) were stirred for 1 h. The reaction mixture was then diluted with EtOAc (60 mL) and Wash several times with brine (50 mL). The aqueous layer is brought with EtOAc (40 mL), and the combined extracts were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by a column of silica gel to obtain a bicyclic alcohol. Bicyclic alcohol, N, N 'carbonate - disuccinimidyl (890 mg, 3.48 mmol), and Et3N (585 mg, 5.8 mmol) were subjected to the same conditions as in the preparation of compound 15 to provide compound 16 (573 mg, 73%, two steps) [] 2"':; +22 5 °, c, 1 6, MeOH: H NMR (CDC1, 200 MH 2) d 5 76 (d, 1H, J = 5 2 Hz) 5 25 (m, 1H), 3 9 -4 3 (m, 4H), 3 14 (m, 1H), 2 85 (s, 4H), 1 9-2 2 (m, 2H) Synthesis of the carbonates (18) and (20) mixed with pyridyl 17 18 Explanation (a) NaBH4, MeOH, 0 ° C, 15 minutes, (b) DSC, Et3N, CH3CN, 1 hour, 90% during two steps 2,5-dioxo-pyrrolidin-1-ylster pyridin-3-ylmetilester from carbonic acid (18) To compound 17 (430 mg, 4 mmol) in MeOH (10 mL) at 0 ° C was added NaBH 4 (279 mg, 8 mg). mmol) in one portion After 15 minutes, the reaction mixture was diluted with EtOAc (20 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous Na 2 SO.sub.2, then concentrated under reduced pressure to obtain an alcohol, which was filtered through a column of silica gel, then concentrated The above alcohol, α, β-disuccinimidyl carbonate (1 47 g, 76 dimentional), and Et3N (606 mg, 6 mmol) in CH CN (10 mL) were stirred for 1 hour. The reaction mixture was then diluted with EtOAc (20 mL) and washed several times with water, and dried over anhydrous Na2SCu. The crude product was purified by column on silica gel. to obtain compound 18 (900 mg, 90%, two steps) This carbonate was unstable and was used immediately 2, 5-dioxo-pyrrolidin-1-ylster pyridin-4-ylmetilester from carbonic acid (20) To compound 19 (400 mg, 3 7 mmol) in MeOH (10 mL) at 0 ° C was added NaBH 4 (236 mg, 7%). 4 mmol) in one portion following the conditions used in the preparation of compound 18 to obtain an alcohol which is filtered through a column of silica gel, then concentrated. The alcohol, carbonate of?,? - disuccimmidi lo (1 4 g, 5 mmol), and Et3 (606 mg, 6 mmol) in CH3CN (10 mL) were allowed to react under the same conditions used in the preparation of compound 18 to obtain compound 20 (824 mg, 88%, two steps) This carbonate was also unstable and was used immediately (3S) -2,5-dioxo-pyrrolidin-1-ylster of tetrahydrofuran-3-yl ter of carbonic acid (22) 21 22 Explanation (b) DSC, Et3N, CH -. CN, 12 hours, 92% Compound 21 (250 mg, 2 84 mmol), β, '- disuccinimidyl carbonate (799 mg, 3 12 mmol), and Et3 ( 431 mg, 4 27 mmol) in CH 3 CN (5 mL) was stirred for 12 hours at room temperature. Then the reaction mixture was diluted with EtO / Ac (20 mL), washed with brine, then concentrated under reduced pressure to obtain Compound 22 (595 mg, 92%) as a solid PF 97-99 ° C 1-. { 3-Hydroxypropyl) -2- (tetra-idropyran-2-yloxy) cyclopentanol (25) 23 24 25 26 Explanation (a) DHP, CH.::C12, 1 5 hours 63%, (b) bromide at 11 lmagne s ?? , THF, 0 ° C, 73%, (c) 9-BBN, THF, 12 hours, then MeOH, H202, aOH, 650 ° C, 1 hour 68%, (d) MsCl, Py, 12 hours, (e ) TsOH, MeOH, 60 minutes 60%, (f) DSC, Et 3 N, CH 3 CN, 12 hours, 40% Compound 24 (13 g, 13 mmol) and dihydropyran (DHP) (1 42 g, 16 9 mmol) in CH2C12 (25 mL) was stirred for 1 5 hours. Aqueous NaHCOj (10 mL) was added, and the reaction mixture was extracted with CH2C12 (10 mL). The combined extracts were dried over anhydrous N2SO4 and concentrated under high pressure. The purification of the crude product by chromatography on silica gel provided the protected THP hydroxyketone (540 mg, 63%) as an oil? NMR (CDC13, 200 MHz) d 5 9 (m, 1 H), 5 1 (m, 2 H), 1 (m, 1 H), 3 9 (m, 2 H), 3 5 (m, 1 H), 2 1- 2 5 (m, 2H), 1 3-2 0 (m, 12H) The ketone (500 mg, 2.7 mmol) in THF (10 mL) was cooled to 0 ° C, and allylmagnesium bromide was added dropwise. (5 4 mL, 5 mmol) After 3 hours at room temperature, the reaction mixture was treated with aqueous NH 4 Cl (10 mL), then diluted with EtOAc (20 mL). The organic layer was washed with brine and dried Na2SO4. The solvents were evaporated under reduced pressure and the crude product was purified by column on silica gel to obtain a mixture of diastereomers (443 mg, 73%) as an oil. The mixture (260 mg, 15 mmol) ) and 9-BBN (9-borabicyclo [3 3 1] nona no) (9 2 mL, 4 6 mmol, 0 5M solution) in THF at 0 ° C was stirred for 12 hours at room temperature MeOH (0 3 mL) , hydrogen peroxide (H20-) (2 5 mL, 30%), Ma OH (7 mL, 30%) were heated at 65 ° C for 1 hour. After cooling to room temperature, the solv The components were evaporated under reduced pressure and the crude product was purified by column on silica gel to obtain compound 25 (191 mg, 68%) as an oil * H NMR (CDC13, 400 MHz) d 4 7 (m, 1H) , 3 8, 3 7, and 3 5 (three m, 5H), 2 5 (br s, 2H), 1 4-2 (m, 16H) 2, 5-dioxo-pyrrolidin-1-ylster 1-oxa-spiro [4 4] non-6-ilester of carbon dioxide (26) To diol 25 (170 mg, 0 69 mmol) and pyridine (1 mL) was added The mixture was stirred for 12 hours, then the mixture was diluted with water, and the mixture was stirred for 12 hours.
EtOAc (10 mL) and the organic layer was washed with brine, dried over anhydrous a2SO4 and concentrated under reduced pressure. The crude cyclic ether was purified by column on silica gel to obtain (111 mg, 71%) of the cyclic product: ? NMR (C DC 13, 400 MHz) 5 71 (m, 1H), 3 95 (m, 4H), 3 87 (m, 1H), 1 6-2 (m, 16H) To the previous ether (110 mg, 0 48 mmol) in MeOH (5 mL) was added p-to luensu 1 f on i co (TsOH) (16 mg) After stirring for 30 minutes, the solvent was evaporated and the crude product was brought up with EtOAc (2 x 10 mL) and the organic layers were washed with brine (10 mL) and concentrated. Purification by column on silica gel provided the spi ro-1 coho 1 (41 mg, 60%) as an oil! H NMR (CDC13, 400 MHz) 6 4 1 (m, 1H), 3 7 (m, 2H), 1 5-2 (m, 10H) The previous spiro-alcohol (27 mg, 0 19 mmol), the carbonate, N '-di S ucc mimi di 1 o (52 mg, 0 204 mmol), Et 3 N (25 mg, 0 25 mmol) in CH 3 CN (5 mL) were stirred for 12 hours, following the same conditions as described for compound 22 to obtain the compound 26 (22 mg, 40%) X H NMR (CDCl 3, 200 MHz) 5 4 7 (m, 1 H), 3 8 (m, 2 H), 2 8 (s, 4 H), 1 5-2 1 (m, 10H) (2S) -2,5-dioxo-pyrrolidin-1-ylster 2-oxo-thiazolidin-4-ylmetilester of carbonic acid (29) Explanation (a) (COCI) -, KOH, water, 2 hours, (b) EtOH, concentrated HCl, 12 hours, 20%, two steps (c) NaBH, MeOH 3 hours (a) DSC, Et3N, CH3CN, 12 Compound 27 (2 42 g, 20 mmol) and potassium hydroxide (KOH) (40%, 5 raL) in water (30 mL), at 0 ° C, was added oxalyl chloride ((COCI) :.) (13 mL, 20%) After stirring for 2 hours, the biphasic layer was placed in a separatory funnel The organic layer was discarded and the aqueous layer was washed with ether (10 mL), then acidified to pHl with 10% HC1 (20 mL) The water was then evaporated under reduced pressure The solid residue was extracted with hot ethanol (EtOH) (4 x 25 mL) The EtOH layer was concentrated to 20 mL and 0 2 mL of concentrated HC1 was added, followed by stirring for 12 hours. The ethanol was then evaporated and the crude product was extracted with EtOAc (2 x 25 mL). The concentration and purification by column on silica gel provided the ethyl ester (668). mg, 20%, two steps) as an oil The ethyl ester was subjected to reduction with NaBHj (2-3 equiv) in MeOH for 2-3 at room temperature to obtain alcohol 28 The treatment of alcohol 28 with N, N- carbonate disuccinimidyl (2 equiv) and E 1 N (4 equiv) in CH CN for 12-24 hours gave the mixed carbonate 29 in excellent yield Explanation (a) NaBH4, MeOH, 0 ° C, 12 hours quantitative, (b) DSC, Et3N, CH CN, 1 hour, 58% over two steps To compound 30 (300 mg, 2 mmol) in MeOH (5 mL) At 0 ° C, NaBHj (145 mg, 3.8 mmol) was added. The resulting mixture was stirred for 12 hours. Standard work and purification gave the corresponding alcohol in quantitative yield The alcohol (50 mg, 0 31 mmol), N, '-disuccimidyl carbonate (1128 mg, 0 5 mmol), and Et 3 N (63 mg, 63 mmol) in CH 3 CN (2 mL) were stirred for 12 hours after Dilution with EtOAc (10 mL) and washing several times with brine (3 x 10 mL), the organic layer was dried over anhydrous NaSO 4 and concentrated under reduced pressure. The crude product was purified by gel chromatography. silica to obtain compound 31 (52 mg, 58%) as a solid PF 94 ° C: HNR (CDC13, 400 MH z) 8 8 9 (d, 1H, J = 4 4 Hz), 8 1 (d, 1H , J = 8 5 Hz), 7 9 (d, 1H, J = 8 3 Hz), 7 74 (m, 1H) 7 63 (m, 1H), 7 49 (d, 1H, J = 4 3 Hz) , 2 84 (s, 4H) 3- (Tetrahydropyran-2-yloxy) benzenesulfonyl chloride (33) Explanation (a) NaN0 :, H; SO.;,?, - ?, 0 ° C, 30 minutes, (b) S0C12, DMF, reflux, 4 hours, (c) DHP, PPTS, CH2C12, 1 hour A solution of compound 32 (5 g, 29 mmol) and sulfuric acid (H2SO4) (8 6 g, 88 mmol) in water (100 mL) at 0 ° C was added sodium nitrite (NaN02) (2 2 g, 32 mmol) ) in portions Then the reaction mixture was stirred for 30 minutes at room temperature, followed by boiling for 20 minutes The red solution was concentrated under reduced pressure The resulting crude product was extracted with hot EtOH (2 x 100 mL) All extractions were concentrated and treated with aqueous NaOH solution until basic, and again concentrated to provide the sodium salt of the crude 3-hydroxybenzenesulfonic acid The salt (5 6 g, 29 mmol) and thionyl chloride (SOCl); (15 mL) were brought to reflux, and dimethyl formamide (DMF) (0 1 mL) was added. The reflux was continued for 4 hours. The reaction mixture was then cooled to room temperature. The mixture was diluted with EtOAc (100 mL), and the organic layer was washed with brine (2 x 50 mL). The combined organic layer was dried over anhydrous NaSO 4 and evaporated under reduced pressure. Purification of the resulting crude product by chromatography on Instantaneous silica gel provided the hydroxybenzenesulfonyl chloride to the sulfonyl chloride (Ig, 5.2 mmol) and DHP (0 87 g, 10 mmol) in CH2C1: (25 mL) was added PPTS (pyridinium p-toluensulfonate) (100 mg) The reaction mixture was stirred for 1 hour at room temperature Then the reaction mixture was diluted with CH2Cl2 (20 mL) and the organic layer was washed with aqueous NaHCOs solution (20 mL) and brine (2 x 20 mL) The combined organic layer was dried over anhydrous S04 and evaporated under reduced pressure. crude product resulting by flash silica gel chromatography afforded compound 33 (670 mg, 56%) X H NMR (C DC 13, 200 MHz) d 7 67 (m, 1 H), 55 (m, 1 H), 7 (m, 1H), 5 5 (m, 1H), 3 9 and 3 6 (two m, 2H), 1 5-2 (m, 6H) Bisacetoxy-toluenesulfonyl chlorides (35), (37), and (37b) 35 Explanation (a) H2S0, Ac20, AcOH, CrC, 0 ° C-5 ° C, 33% Acetoxy- (4-chlorosulfonylphenyl) methylester of acetic acid (35) To compound 34 (2 g, 10 mmol), H 2 SO 2 (2 g, 21 mmol), Ac: 0 (8 mL), AcOH (8 mL) ) at 0 ° C-5 ° C CrO;, (2 1 g, 21 mmol) was added in portions. The resulting reaction mixture was monitored by TLC. When the reaction was 50% complete, ice cold water (50 mL) was added. ) and the reaction mixture was extracted with EtOAc The organic layer was washed with brine (2 x 20 mL) and then with aqueous NaHC05 solution The combined organic layer was dried over anhydrous a2SO4 and evaporated under reduced pressure Purification of the product crude product by flash silica gel chromatography afforded compound 35 (1 09 g, 33%) X H NMR (CDC 13, 200 MHz) d 8 0 (d, 2 H, J = 6 7 Hz), 7 78 (m, 3H), 2 15 (s, 6H) Acetoxy (3-chlorosulfonylphenyl) methylester of acetic acid (37) The same procedure was followed as for the preparation of compound 35 starting with m-toluene-sulphonyl chloride (36): H NMR (CDC13, 200? ?) d 8 19 (m, 1H), 8 1 (m, 1H), 7 9 (m, 1H), 7 65 (m, 1H), 2 16 (s, 6H) 37a 37b Explanation (a) H2S04, AC20, AcOH, Cr03, 0 ° C-5 ° C, 33% Acetoxy (3-chlorosulfonyl-2-methyl-phenyl) methylester of acetic acid (37b) Following the same reaction under controlled conditions as described for compound 35, a mixture of isomers of compound 37b was obtained 3, 5-Bis- (tetrahydropyran-2-yloxy) -benzenesulfonyl chloride (39) 39 38 Explanation (a) S02, NaHCC > 3, 6 hours then compound 38, reflux, four days, (b) S0 C1, reflux, DMF, 50% during two steps, (c) DHP, PPTS, CH2C12, 1 hour, 67% To a suspension of NaHCO3 ( 10 g, 119 mmol) in water (30 raL) was bubbled S0 gas The bubbling continued until the NaHC03 was solubilized (6 hours) To this yellow solution (the exit gases had a pH 1-2) was added the f lugoglucinol 38 (5 g, 30 mmol) The reaction mixture was refluxed for four days, then cooled to room temperature, the solvent was evaporated, and the resulting solid was dried to obtain 3,5-dihydroxybenzenesulfonic acid. The crude acid (500 mg, 2 35 mmol) and S02C1 (7 raL) were refluxed in the presence of DMF (0 1 mL) for 40 minutes The resulting reaction mixture was extracted with EtOAc (50 mL) and the organic layer was washed with brine (2 x 20 mL) and NaHCOi aqueous The combined organic layers were dried over Na SC > The anhydrous contents were then evaporated under reduced pressure. The purification of the resulting crude product by flash silica gel chromatography afforded the dihydric chloride ibe ncensu 1 f on i 1 (246 mg, 50%) as an oil: H NMR ( CDCl: i, 200 MHz) d 7 1 (m, 2H), 6 8 (m, 1H) The dihydroxy compound (222 mg, 1 06 mmol), DHP (224 mg, 2 66 mmol) in CH C1: ( 10 mL), and PPTS (50 mg) were stirred for 30 minutes at room temperature. Then, the reaction mixture was diluted with CH2C1:; (20 mL), and the organic layer was washed with brine (2 x 20 mL) The combined organic layer was dried over anhydrous a2SO4 and evaporated under reduced pressure The purification of the resulting crude product by instantaneous silica gel chromatography provided the compound 39 (237 mg, 67%) as an oil? NMR (CDCl; i, 300 MHz) 6 7 3 (m, 2H), 7 (m, 1H), 5 4 (m, 2H), 3 8 and 3 6 (two m, 4H), 1 4-2 ( m, 12 H) 5-nitropyridin-3-sulfonyl chloride (42) 40 41 42 Explanation (a) Br :, 130 ° C, 8 hours, (b) H20, 100 ° C, 2 hours, (c) NH4OH, C uSO ,, «5 H;: 0, 170 ° C, 20 hours, ( d) H S04 steaming, H202, 0 ° C-23 ° C, 40 hours, (e) PC15, POCI3, reflux, 6 hours, 45 *. for five steps 5-Bromopyridine-3-sulfonic acid (41) Compound 40 (7 g, 35 mmol) and bromine (6 7 g, 42 mmol) in a sealed tube were heated at 130 ° C for 8 hours in an oil bath. After cooling to room temperature, water (70 mL) was added, and the reaction mixture was again heated to 100 ° C for 2 hours. After cooling, acetone (60 mL) was added and the resulting solid was filtered, and dried to obtain compound 41 as a white solid as crude product "H NMR (dMSO-d6, 300 MHz) d 9 3 (br s, 1H), 8 8 (m, 2H), 8 2 (m, 1H) 5-Nitropyridin-3-sulfonyl chloride (42) The acid 41 (4 5 g, 19 mmol), ammonium hydroxide (NH4OH) (15 mL, 28%), and copper sulfate (CuS04-5H: O) ( 470 mg, 1.9 mmol) were heated at 170 ° C in a sealed tube for 20 hours After cooling, water (5 mL) was added followed by sodium sulfide (Na2S »9H20) (450 mg) Evaporation of the water provided the crude aminopic acid idol sulphonic acid The fuming H2SO4 (30 mL) was placed in a flask cooled to 0 ° C. Hydrogen peroxide (H2O2) (14 mL, 30%) was added, then the crude sulfonic acid above (2.8 g). , 16 mmol) in H 2 SO 4 (8 mL) was added to the above mixture. The resulting solution was stirred at room temperature, for 40 hours, and then empty in sodium carbonate containing ice water. Sufficient Na C05 was added to make the basic solution, which was acidified again to pH 1-2. The resulting solution was concentrated to a minimum volume (20 mL ) The precipitated NaCl was filtered, and the filtrate was concentrated The resulting solid was extracted with MeOH (3 x 50 mL) The combined MeOH extractions were concentrated to 20 mL, and acetone (80 mL) was added The solid obtained was filtered and dried to obtain acid mtropiridm sulfomco This acid (1.7 g, 7 mmol) and phosphorus pentachloride (PC15) (1.7 g, 8 mmol) in POCl? (50 mL) were refluxed for 6 hours After cooling to room temperature, the solids were filtered, and the filtrate was concentrated. The oily residue was diluted with EtOAc (100 mL) and the organic layer was washed with brine (2 x). 20 mL) The combined organic layer was dried over anhydrous NaSO 4 and evaporated to obtain compound 42 (730 mg, 45%) as an oil: H NMR (CDC13, 400 MHz) d 9 15 (m, 1H) ), 9 02 (m, 1H), 8 43 (m, 1H) 4-fluoro-3- chloride? trobenzenesulfonyl (44) 43 44 Explanation (a) H ^ SO ^ steaming, 60 ° C, 30 minutes, quantitative, (b) PCI;., P0C1: ¾, reflux, 6 hours, quantitative To compound 43 (7 g, 5 mmol) was carefully added H2SO4 steaming (60 mL) The resulting mixture was heated at 60 ° C for 30 minutes. Then, the hot mixture was slowly and very slowly emptied into a beaker containing potassium chloride (KC 1) (30 g) and ice solid. Resulting white obtained is recrystallized from hot water to provide the acid 4-f 1 or ro-3-n 11 steal its 1 f on 1 co in quantitative yield The acid (2 g, 7 7 mmol) and phosphorus pentachloride ( PC15) (1.8 g, 7.5 mmol) in phosphorous oxytrichloride (POC13) (60 mL) were brought to reflux for 6 hours. The resulting mixture was cooled to room temperature, and concentrated. Crushed ice was added to the oily residue The solid it was filtered and washed with water (2 x 50 mL), dried to obtain Compound 44 (quantitative) H NMR (CDCl 3, 500 MHz) 6 8 8 (m, 1H) , 8 36 (m, 1H), 7 6 (m, 1H) Synthesis of pyrrolidinamines (46) and (50) Explanation (a) Boc20, CH.:C1 :, 2 hours, (b) p-TsCl, Et3N, DMAP, CHSC1 :, 8 hours, quantitative, (c) N aN 3, DMF, 80 ° C, 4 hours , (d) H2, Pd-C (10%), MeOH, 5-6 hours, 92% Ter-butyl er of (3R) -3-amino-pyrrolidine-l-carboxylic acid (46) Compound 45 (775) mg, 9 mmol) and Boc20 (2 33 g, 10 6 mmol) in CH2C12 (40 mL) were stirred for 2 hours at room temperature. Then, the reaction mixture was diluted with CH2Cl2 (20 mL), and the organic layer was wash with brine (2 x 20 mL) The combined organic layer was dried over anhydrous Na2SO.i and concentrated The purification of the resulting crude product by flash silica gel chromatography afforded N-Boc pyrrolidinol as an oil This alcohol (7 3 g , 39 mmol), p-TsCl (8 2 g, 43 mmol), Et-, N (9 8 g, 97 mmol), DMAP (240 mg) in CH 2 Cl 2 (100 mL) were stirred for 8 hours at room temperature. the reaction mixture was washed with brine (100 mL). The organic layer was dried over anhydrous NaiSO4 and concentrated Purification of the resulting crude product by flash silica gel chromatography afforded the ester in quantitative yield This sulfonate ester (12.5 g, 38 mmol) and NaN3 (3.7 g, 57 mmol) in DMF (70 mL) were heated to 80 °. C for 4 hours After cooling to room temperature, the reaction mixture was diluted with EtOAc (200 mL) The organic layer was washed with brine (2 x 100 mL) The combined organic layer was dried over Na2SC > 4 anhydrous and concentrated The purification of the resulting crude product by flash silica gel chromatography afforded the azido compound, which is hydrogen in the presence of Pd-C (10%) in MeOH for 5-6 hours to obtain compound 46 (7). 43 g, 921) as a JH NMR oil (CDC13, 300 MHz) d 4 12 (m, 1H), 3 5 (m, 4H), 2 (m, 2H), 1 45 (s, 9H) 48 49 NH2 fifty Explanation (a) L1AIH4, THF, 55 ° C, 24 hours, 55%, (b) MsCl, E13N, CH2C1¿, 0 ° C, 45 minutes, 90%, (c) BnNH, reflu or, 36 hours, (d) Pd (OH) 2, Boc20, Et-,?, THF, 8 hours, 85%, (e) TsOH, MeOH, 1 hour 96%, (f) MsCl, Et3N, 0 ° C, CH :: C1 ^, 10 minutes, (g) NaN3, DMF, 80 ° C, 6 hours, (h) H2, Pd-C (10%), MeOH, 5 -6 hours, 81% during two steps 4-Methanesulfonyloxy-3- (tetrahydropyran-2-yloxy) b-tablester of methanesulfonic acid (48) To compound 47 (8 4 g, 34 mmol) in THF (130 mL) was added hydride from 11110 - to 1 umium. (LiAlH4) (7 6 g, 206 mmol) in portions The resulting mixture was heated at 55 ° C for 24 hours. After cooling to room temperature, H.-O (7 2 ml), NaOH (7 2) were added sequentially. mL, 20%), and H20 (14 4 mL) and the mixture was stirred for 12 hours The solid was filtered and the filtrate was concentrated The purification of the resulting crude product by flash silica gel chromatography provided the diol (3 66, 55%) as an oil] H NMR (CDC13, 400 MHz) or 4 6 (m, 1H), 4 (m, 1H), 3 5-3 9 (m, 6H), 2 92 (s, 2 H) , 1 4-1 82 (m, 8H), (s, 9H) To this diol (3 66 g, 19 mmol) and Et 3 N (5 23 g, 51 mmol) in CH 2 Cl;: (80 mL) at 0 ° C was added MsCl (5 48 g, 48 mmol) The resulting reaction mixture was stirred for 45 minutes at room temperature, then the reaction mixture was diluted with CH 2 Cl 2 (50 mL) and the organic layer was washed with brine (2 x 20 mL) The combined organic layer was dried over anhydrous Na 2 SO.sub.1 and concentrated The purification of the resulting crude product by flash silica gel chromatography afforded compound 48 (6 g, 90%) as an oil: H MMR (CDC13, 300 MHz) 4 6 (m, 1H), 4 2-4 4 (m, 4H), 3 8-4 1 (m, 2H), 3 fm, 6H), 2 ( m, 2H), 1 75 (m, 2 H), 1 45 (m, 4H) Ter-butyl ester of 3-hydroxypyrrolidine-l-carboxylic acid (49) Compound 48 (6 g, 17 mmol) and BnNH2 (6 5 g, 60 mmol) in THF (150 mL) were refluxed for 12 hours. Benzylamine (Bn H :) (6 5 g, 60 mmol) was added again and the reflux was continued for 24 hours, followed by cooling to room temperature. The reaction mixture was diluted with EtOAc (100 mL) and the organic layer was washed. with brine (2 x 20 mL) The combined organic layer was dried over anhydrous Na-SC and concentrated The purification of the resulting crude product by flash silica gel chromatography afforded the pyrrolidine compound (4 4g) as an oil: H NMR (CDC13, 300 MHz) d 7 2 (m, 5H), 4 55 (m, 1H), 4 38 (m, 1H), 3 8 (m, 1H), 3 6 (m, 2H), 3 41 ( m, 1H), 2 4-2 7 (m, 4H), 2 1 (m, 1H), 1 4-1 9 (m, 7H) This amino compound (4 4 g, 17 mmol) in MeOH (50 mL ) was hydrogenated over Pd (OH) - (1 g, 20%) for 18 hours BociO (4 4 g, 20 mmol) and Et: iN (3 g, 21 mmo) were added. 1) and stirred for 8 hours at room temperature. The reaction mixture was diluted with EtOAc (100 mL) and the organic layer was washed with brine (2 x 20 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated. purification of the resulting crude product by flash silica gel chromatography afforded the Boc compound (3.9 g, 85%) to this THP ether (3.9 g, 14.3 mmol) in MeOH (60 mL) was added TsOH (140 rag), followed by stirring for 1 hour at room temperature. Then the reaction mixture was diluted with EtOAc (100 mL) and the organic layer was washed with brine (2 x 20 mL). The combined organic was dried over anhydrous Na2SO4 and concentrated. Purification of the resulting crude product by flash silica gel chromatography afforded compound 49 (2 56, 96%) [a] D25 +24 2 o, c, 2 1, CHC13? NMR (CDC13, 300 MHz) d 4 4 (m, 1 H), 3 4 (m, 3 H), 3 3 (m, 1 H), 1 89 (m, 2 H), 1 4 (m, 9 H) Ter-butyl ester of (3S) -3-aminopyrrolidine-l-carboxylic acid (50) To compound 49 (g, 10 7 mmol) and Et3N (2 15 g, 21 mmol) in CH2C12 (50 mL) at 0 ° C add MsCl (1 46 g, 12 8 mmol), followed by stirring for 10 minutes at room temperature. Then the reaction mixture was diluted with CH 2 Cl 2 (50 mL) and the organic layer was washed with brine (2 x 50 mL). The combined organic was dried over anhydrous Na2SO4 and concentrated The purification of the resulting crude product by flash silica gel chromatography afforded the dimesolate compound (2.9 g) as an oil This mesolate (2.9 g, 11 mmol) and NaN3 (1 g, 16 mmol) in DMF (20 mL) were stirred for 6 hours at 60 ° C. Then the reaction mixture was diluted with EtOAc (50 mL) and the organic layer was washed with brine (2 x 20 mL). The combined organic layer was dried over a ^ SC anhydrous and concentrated. Purification of the resulting crude product by flash silica gel chromatography provided a azido compound, which was hydrogenated as described above to provide compound 50 (1 87 g, 81%) as an NMR oil (CDC13, 400 MHz) d 4 12 (m, 1 H), 3 4 (m, 4H) (m, 2H), 1 45 (s, 9H) Ter-butyl ester of 3-aminoazetidine carboxylic acid (53) 51 52 53 Explanation (a) ben zh i dr i 1 amine, MeOH, 72 hours, 23 ° C, then reflux 72 hours, (b) MeOH, EtOH (1 1), Pd (OH) 2 (20%), 12 hours , (c) Boc20, saturated NaHCOj, 24 hours, (d) MsCl, Et3M, CH2C12, 1 hour, 83%, (e) NaNj, DMF, 70 ° C, 72 hours, then H2 / Pd-C (10% ), MeOH, 5-6 hours, quantitative Ter-butyl ester of 3-hydroxyazetidine-l-carboxylic acid (52) 2- (2-Chloroethyl) oxirane (51) (5 g, 54 mmol) and ben zhid i lamina (10 g, 53 mmol) in MeOH (25 g) mL) were left to stand for 72 hours, then brought to reflux for 72 hours. The reaction mixture was cooled to room temperature, then concentrated to obtain a solid of the crude product.
The crude product (1.7 g, 7 mmol), in MeOH and EtOH (10 + 10 mL), is hydrogenated in the presence of Pd (0H) 2 (500 mg, 20%) for 12 hours. The reaction mixture is then filtered. , and Boc was added; 0 (2 3 g, 10 mmol) and saturated NaHCOj solution (10 mL), followed by stirring for 24 hours at room temperature. Then the reaction mixture was diluted with EtOAc (50 mL) and the organic layer was washed with brine. (2 x 20 mL) The combined organic layer was dried over anhydrous Na 2 SO 5 and concentrated The purification of the resulting crude product by flash silica gel chromatography afforded compound 52 (1 35g) H NMR (CDC 13, 300 MHz) 6 4 (m, 1H), 4 04 (m, 2H), 3 7 (dd, 2H), 1 45 (s, 9H) 3-aminoazetidin-l-carboxylic acid tert-butyl ester (53) To compound 52 (928 mg, 5 3 mmol) and Et.jN (lg, 10 7 mmol) in CHCl3 (20 mL) was added MsCl (733) mg, 6 mmol), followed by stirring for 1 hat room temperature. Then the reaction mixture was diluted with CH2 I2 (20 mL) and the organic layer was washed with brine (20 mL). The combined organic layer was dried over Na ^ SO ^ anhydrous and concentrated The purification of the resulting crude product by flash silica gel chromatography afforded the mesolate compound (11 11 g, 83%) as an oil mesolate (11 g, 4 4 ramol) and NaN3 ( 574 mg, 8 mmol) in DMF (10 mL) was stirred for 12 h at 72 ° C. The reaction mixture was then diluted with EtOAc (20 mL), and the organic layer was washed with brine (2 x 20 mL) The combined organic layer was dried over anhydrous Na: SO 4 and concentrated. Purification of the resulting crude product by flash silica gel chromatography. or the azido compound, which was subsequently converted to compound 53 in quantitative yield by hydrogenation? NMR (CDC13, 300 Hz) d 4 15 (m, 3H), 3 82 (m, 2H), 1 4 (s, 9H) 3-Aminotetrah3.drofuran (55) 54 55 Explanation (a) MsCl, E 13 N, C H2C 12, 1 h (b) aN 3, DMF, 7Q ° C, 72 h, (c) H2, Pd-C (10%), MeOH, 5 -6 h, quantitative The same reaction conditions used to prepare compound 53 were used to obtain compound 55 in quantitative yield. A satisfactory NMR was obtained for this compound 3,5-Bis- (tetrahydropyran-2-yloxy) benzenesulfonyl chloride (57) E (a) aminosulphonic acid, 180-200 ° C, 1 5 h, 40%, (b) SO-Cl, reflux, DMF, 1 h 44%, (c) DHP, PPTS, CH2C1;, 2 h , 56% Compound 56 (25 g, 220 mmol) was heated to 180-200 ° C, then ammonium phonic acid (9 7 g, 100 mmol) was added in portions The resulting suspension was stirred and heated for 1 5 h , then cooled, and dissolved in a minimum amount of water The clear solution was treated with decolorizing charcoal and filtered The filtrate was washed with ether (2 x 50 mL), and the aqueous layer was concentrated to a minimum volume ( 20 mL) On standing the crystals were separated, they were dried to obtain 3,4-dihydroxybenzenesulfonic acid (7 56 g, 40%) PF 254-255 ° C, lit 260 ° C to the above sulfonic acid (7 g, 38 mmol), SOCl ^ (15 mL) and DMF (0 1 mL) were added following the same conditions described above for compound 39 to obtain sulfonyl chloride (3.6 g, 44%) as an oil This chloride (3%) g, 16 8 mmol), DHP (3 Ig, 37 mmol), and PPTS (200 mg) in CH: C12 (50 mL) were stirred for 2 h at room temperature. Then the reaction mixture was diluted with CH2Cl2 (20 mL) and the organic layer was washed with NaHCO3 ( 20 mL), then brine (2 x 20 mL) The combined organic layer was dried over anhydrous and concentrated The purification of the resulting crude product by flash silica gel chromatography afforded compound 57 (3 2 g, 56%) as a JH NMR oil (CDC13, 200 MHz) d 8 (d, 1H, J = 2 Hz), 7 63 (m, 1H), 7 25 (d, 1H, J = 8 4 Hz), 5 58 (m, 2H ), 3 4-4 2 (m, 4H), 1 4-2 2 (m, 12H) Synthesis of mixed carbonates of spirocycles 61 Explanation (a) DHP, PPTS, CH C12, 4-5 h, (b) K2C03, MeOH, 30 minutes, (c) Rh / Al202, H2, EtOAc, 8-12 h, (d) BnBr, NaH, TBAI , THF, 12-14 h, (e) p-TsOH, MeOH, 20-30 minutes, (f) PCC, CH2C12, MS (4A), 12 h, (g) allylmagnesium bromide, THF, 0 ° C, 30 minutes, (h) 9BBN, THF, room temperature 24 h, (1) MsCl, Py, 24 h, (3) H, Pd (OH) EtOAc, 12 h, (k) carbonate, N-di succin Im 1 di, Et3, Nitrile aceto, 12-24 h The same conditions were followed for the synthesis of the mixed carbonate 63 62 63 Variation of the p2 ligands of the hydroxybenzenesulfonamide isostere i-R = 0THP R = H Explanation (a) I obut 11 amine, isopropanol, reflux, 6 h, (b) sulphonyl chloride 33, CH2CI2, aqueous NaHCO3 solution, 12 h, (c) Pd-C (10%), H2, MeOH , 6-8 h, (d) various mixed carbonates, Et3N, CH2C12, 4-6 h Compound 75: compound 66 (012 mmol), compound 26 (014 mmol), and Et¾N (2 equiv) in CH2Cl2 (1 mL) were stirred for 6 hours at room temperature. The reaction mixture was diluted with CH2C12 (10 mL). mL) and the organic layer was washed with brine (2 x 20 mL) The combined organic layer was dried over anhydrous Na2SO and concentrated The purification of the resulting crude product by flash silica gel chromatography provided the THP ether THP ether (O. 011 mmol) and p-TsOH (2 mg) in MeOH (0 5 raL) were stirred for 10 minutes at room temperature. Then the reaction mixture was diluted with EtOAc (10 mL) and the organic layer was washed with brine (2 x). 20 mL) The combined organic layer was dried over anhydrous NatS04 and concentrated The purification of the resulting crude product by flash silica gel chromatography afforded compound 75 (5 mg) as a solid; H NMR (CDC13, 400 MHz) d 8 3 (s, 1H), 7-7 4 (m, 9H), 5 05 (m, 1H), 4 68 (d, 1H, 4 Hz), 3 8-4 (m, 3H), 3 6 (m, 1H), 2 6-3 1 (m, 6H), 1 5-2 1 (m, 1H), 0 93 (m, 6H) Compound 78 Compound 66 (22 mg, 0 055 mmol), Compound 4 (18 mg, 0 066 mmol), and Et 3 N (2 equiv) in CH 2 Cl 2 (1 mL) were subjected to the same conditions as described above for the compound 75 to obtain compound 78 (23 mg) as a solid lti NMR (CDC13, 400 MHz) 6 7 2-7 5 (m, 9H), 5 5 (m, 1H), 4 86 (m, 2H), 4 4 (m, 1H), 3 6-3 8 (m, 6H), 2 8-3 2 (m, 6H), 2 6 (m, 1H), 1 4-2 1 (m, 13H), 0 96 (ABq, 6H, J = 6 5 Hz) Compound 79 Compound 78 (19 mg, 0 03 mmol) and TsOH (6 mg) in MeOH (1 mL) were subjected to the same conditions as described above for compound 75 to obtain compound 79 (12 mg) as a solid H NMR (C DC 13, 400 MHz) d 8 9 (s, 1 H), 7 1-7 4 (m, 8 H), 7 03 (d, 1 H, J = 6 9 Hz), 5 29 (m, 1 H), 5 (d, 1 H , J = 8 8 Hz), 4 6 (t, 1H, J = 6 1 Hz), 4 1 (m, 1H), 3 85-4 (m, 2H), 3 75 (q, 1H, J = 7 9 Hz), 3 53 (dd, 1H, J = 3 Hz, 15 Hz), 3 1 (m, 1H), 2 91 (dd, 1H, J = 5 2 Hz, 14 Hz), 2 82 (m, 1H), 2 65 (dd, 1H, J = 7 6 Hz, 14 9 Hz), 2 59 (dd, 1H, J = 4 6 Hz, 13 1 Hz), 1 7-2 2 (m, 7H), 0 98 and 0 88 (ABq, 6H, J = 6 4 Hz) Variation of the p2 ligands of the 2,4-dihydroxybenzenesulfonamide isostere R = H Explanation a) I Sobutylamine, isopropanol, reflux, 6 hours, b) sulfonyl chloride 39, CH2C1; aqueous solution, NaHC03, 12 hours, c) Pd-C (10%), H2, MeOH, 6 hours , d) mixed carbonate, Et3N, CH2C12, 2-3 hours, e) p-TsOH, MeOH, 5-15 minutes Compound 87 Compound 80 (55 mg, 0 9 mmol), compound 4 (25 mg, 0 9 mmol), and Et3N (2.0 equiv) in CH; Cl2 (2 mL) were subjected to the same conditions as described above for compound 75 to obtain compound 87 (26 mg) as a solid? NMR (CDC13, 400 MHz) d 7 2-7 5 (m, 8 H), 5 56 (m, 2 H), 4 86 (m, 2 H), 4 3 (m, 1 H), 3 5-4 (m, 8H), 2 8-3 2 (m, 6H), 2 6 (m, 1H), 1 6-2 1 (m, 19H), 0 86 (ABq, 6H, J = 6 3 Hz) Compound 88 the compound 87 (21 mg, 0 028 mmol) and p-TsOH (10 mg) in MeOH (1 mL) were subjected to the same conditions as described above for compound 75 to obtain compound 88 (8 mg) as a solid PF 80-82 ° C [a] D 25 +9 7o, c, 0 82, MeOH lti NMR (CDClj, 400 MHz) 5 9 5 (s, 1H), 7 2 (m, 7H), 7 (d, 1H, J = 8 3 Hz), 6 (s, 1H), 5 03 (t, 1H, J = 5 2 Hz), 4 91 (d, 1H, J = 8 9 Hz), 4 58 (t, 1H, J = 6 2 Hz), 4 18 (dd, 1H, J = 6 5 Hz, 7 7 Hz), 3 9 (m, 2H), 3 82 (m, 1H), 3 51 (dd, 1H, J = 3 5 Hz, 15 Hz), 3 25 (m, 1 H), 3 1 (m, 2 H), 2 95 (dd, 1 H, J = 8 2 Hz, 14 Hz), 2 87 (m, 1 H), 2 58 (m, 1H), 2 49 (dd, 1H, J = 4 3 Hz, 13 Hz), 1 9-2 2 (m, 4H), 1 75 (d, 1H, J = 14 2 Hz), 1 02 and 0 87 (ABq, 6H, 6 4 Hz) Variation of the p2 ligands of 3,5-dihydroxybenzenesulfonamide isosteres Explanation a) Isobutylamine, isopropanol, reflux, 6 hours, b) sulfonyl chloride 39 Na HC0? aqueous, CH C1, 12 hours, c) Pd-C (10%), H2, MeOH, 6 hours, d) various mixed carbonates, Et3N, CH2C12, 6 hours, e) p-TsOH, MeOH, 5-15 minutes Compound 99 Compound 89 (102 mg, 178 mmol), Compound 4 (48 mg, 178 mmol), and Et 3 N (20 equiv) in CH 2 Cl (5 mL) were subjected to the same conditions as described above for Compound 75 to obtain compound 99 (110 mg) as a solid: H NMR (CDC13, 400 MHz) d 7 25 (m, 5H), 7 09 (s, 2H), 6 96 (s, 1H), 43 (m, 2H), 4 78 (m, 2H), 4 39 (m, 1H), 3 9 (m, 5H), 3 65 (m, 3H), 3 15 (m, 2H), 3 05 ( m, 1H), 2 87 (m, 2H), 2 6 (m, 1H), 2 02, 1 85 and 1 7 (three m, 18 H), 0 92 and 0 87 (ABq, 6H, J = 6 4 Hz) Compound 100 Compound 99 (88 mg, 12 mmol) and TsOH (20 mg) in MeOH (5 mL) were subjected to the same conditions as described above for compound 75 to obtain compound 100 as a solid Lti. NMR (CDC13, 200 MHz) d 8 08 (s, 2H), 7 23 (m, 5H), 6 78 (s, 2H), 6 54 (s, 1H), 5 21 (d, 1H, J = 8 Hz), 4 93 (m, 1H), 4 52 (m, 1H), 3 8-4 1 (m, 3H), 3 68 (dd, 1H, J = 7 Hz, 14 5 Hz), 3 5 (m, 2H), 2 5-3 1 (m, 7H), 1 5-2 2 (m, 7H), 0 92 and 0 89 (ABq, 6H, J = 6 4 Hz) Incorporation of high affinity p2 ligands into a novel class of hydroxyethylamine isostere Explanation a) I sheet, isopropanol, reflux, 6 hours, b) sulfonyl chloride 35, aqueous NaHCO3, CH2C12, 12 hours, c) K2CO0 MeOH, 30 minutes, d) NaBHj, MeOH, 15 minutes, e) Pd -C (10%), H2, MeOH, 6 hours, f) various mixed carbonates, Et;., N, CH2C12, 6 hours Compound 110 Compound 101 (70 mg, 0 17 mraol), compound 4 (46 mg, 0 17 mmol), and Et 3 (20 equiv) in CH, Cl 2 (10 mL) were subjected to the same conditions as described. described above for compound 75 to obtain compound 110 (75 mg) as a solid PF 110-112 ° C [alv + 10 °, c, 0 72, CHCl 3] H NMR < CDC1, 400 MHz) 5 7 75 (d, 2H), 7 5 (d, 2H), 4 85 (s, 1H), 4 76 (m, 3H), 4 37 (m, 1H), 3 6-3 9 (m, 4H), 2 8- 3 15 (m, 6H), 2 6 (m, 1H), 2 (m, 2H), 1 8 (m, 2H), 1 69, 1 55, and 1 44 (three m, 3H), 0 89 (ABq, 6H, J = 6 4 Hz) Compound 111 Compound 101 and Compound 6 were subjected to the conditions described above for compound 75 to obtain 111 as a solid XH NMR (CDC13, 300 MHz) d 7 76 (d, 2H, J = 8 Hz), 7 42 (d, 2H, J = 3 1 Hz), 7 2 (m, 5H), 4 8 (m, 1H), 4 77 (s, 2H), 4 66 (m, 1H), 4 35 (m, 1H), 3 6-3 82 (m, 4H), 2 71-3 05 (m, 6H), 2 6 (m, 1H), 1 4-2 1 (m, 6H), 0 82 (ABq, 6H, J = 6 4 Hz) Compound 113 Compound 112 and Compound 4 were subjected to the conditions described above for compound 75 to obtain 113 as a solid [a] L, '' r +4 4 ° C, c, 0 67, CHCl 3 J H NMR (CDCl 3, 300 MHz) 8 (s, 1 H), 7 61 (d, 1 H, J = 10 Hz), 7 44 (m, 2 H), 7 21 (m, 5 H) ), 4 92 (d, 1H, J = 10 8 Hz), 4 81 (m, 1H), 4 71 (s, 2H), 4 38 (m, lH) r 3 6-3 91 (m, 3H) , 3 39 (m, 1H), 3 01 (m, 3H), 2 92 (d, 2H, J = 10 Hz), 2 5- 2 8 (m, 2H), 1 78-2 02 (m, 5H ), 1 4-1 65 (m, 2H), OR 91 (ABq, 6H, J = 6 3 Hz) Compound 114 Compound 112 and compound 15 were subjected to the conditions as described above for compound 75 to obtain 114 as a solid LH MR (CDCl- =, 400 MH) d 7 15-7 65 (m, 9H ), 5 6 (d, 1H, J = 5 1 Hz), 5 54 (d, 1H, J = 9 2 Hz), 4 96 (m, 1H), 4 69 (s, 2H), 3 57-3 83 (m, 6H), 2 72-3 2 (m, 7H), 1 9, 1 32 and 1 26 (three m, 3H), 0 88 (ABq, 6H, J = 6 4 Hz) Bis-THF as the ligand p2 in the hydroxyethylsulfonamide isostere with variation in the pl1 region Explanation a) íBuNH;, íPrOH, reflux, 6 hours, b) sulfonyl chloride 35 or 36, aqueous NaHC03, CH2C1 :, 12 hours, c) Pd-C (10%), MeOH, 6-8 hours, d) K2C03, MeOH, 30 minutes, c) H, Pd-C (10%), mixed carbonate 15, Et 3N, THF, 12 hours, d) (i) NaBHl, EtOH, (n) TsCl, Et3N, DMAP for compound 117, e) reductive animation (NaCNBH4, AcOH, MeOH), with NH4OAc for compound 118, with MeNH2 for compound 119, f) NH2OH, HC1, Et3N, MeOH, for compound 120, g) (i) tri Phen i 1 phon-a ce t at o, NaH, THF, 0 ° C, 30 minutes, (n) DIBAL-H, CH2C12, -78 ° C, 1 hour for compound 121 ?? Compound 117 compound 116 was subjected to reduction with N to BH. <; and the resulting alcohol was treated with pTsCl in pyridine to obtain compound 117 as an oil 1ti NM (CDC13, 400 MHz) 6 7 79 (d, 2H, J = 8 Hz), 7 74 (d, 2H, J = 8 4 Hz), 7 43 (d, 2H, J = 8 Hz), 7 36 (d, 2H, J = 8 4 Hz), 7 23 (m, 5H), 5 64 (d, 1H, J = 5 2 Hz), 5 1 (s, 2H), 5 02 (m, 2H), 3 8-4 (m, 3H), 3 7 (m, 2H), 3 61 (m, 1H), 2 75-3 2 (m, 7H), 2 45 (s, 3H), 1 45, 1 6, and 1 83 (three m, 3H), 0 89 (ABq, 6H, J = 6 4 Hz) Compound 118 the compound 117 (26 mg, 0 036 mmol) and NaN3 (5 mg, 073 mmol) in DMF (2 mL) were stirred for 30 minutes at 65-70 ° C. Then the reaction mixture was diluted with EtOAc (20 mL) and the organic layer washed with brine (2 x 20 mL) The combined organic layer was dried over NaSO, anhydrous and concentrated The purification of the resulting crude product by flash silica gel chromatography afforded an azido intermediate The azido intermediate (21 mg, 0 036 mmol) and trifluorophosphine (Ph3P) (14 mg, 0.054 mmol) in THF »H20 (9 1.2 mL) were added. The mixture was stirred for 12 hours at room temperature. The reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed with brine (2 x 20 mL). The combined organic layer was dried over anhydrous Na 2 SO.sub.1 and concentrated. Resulting crude product by flash silica gel chromatography afforded compound 118 as a solid: H NMR (CDC1, 200 MHz) d 7 75 (d, 2H, J = 8 2 Hz), 7 51 (d, 2H, J = 8 Hz), 7 23 (m, 5H), 5 65 (d, 1H, J = 5 2 Hz), 4 99 (m, 2H), 3 62-4 1 (m, 6H), 2 73-3 2 (m, 7H1, 1 85 (m, 1H), 1 6 (m, 2H), 0 91 (ABq, 6H, J = 6 4 Hz ) Compound 119 to compound 116 (75 mg, 0 133 mmol), methylamma (MeNH :;) (8 3 mg, 0 026 mmol), and acetic acid (AcOH) (9 5 mg, 0 015 mmol) in MeOH (5 mL) was added sodium cyanoborohydride (NaCNBH, ,) (10 mg, 0.159 mmol) at room temperature The resulting reaction mixture was stirred for 12 hours at room temperature. Then the reaction mixture was diluted with EtOAc (20 mL) and NaHCO3 solution (5 mL). The organic layer washed with brine (2 x 20 mL) The combined organic layer was dried over Na; SCu anhydrous and concentrated The purification of the resulting crude product by flash silica gel chromatography afforded compound 119 as a solid PF 57-62 ° C 1tt NMR (CDC13, 400 MHz) d 7 75 (d, 2H, J = 7 6 Hz), 7 75 (d, 2H, J = 8 Hz), 5 64 (d, 1H, J = 5 2 Hz), 5 03 (m, 2H), 3 8-4 (m, 5H), 3 88 (s, 2H), 3 67 (ra, 1H), 2 75-3 2 (m, 7H), 1 44, 1 63 , and 1 93 (three m, 3H), 0 89 (ABq, 6H, J = 6 4 Hz) Compound 120 the previous azide epoxide was converted to the corresponding aldehyde using the sig sequence sequence i) terminal epoxide with isobutyl lamina in isopropyl alcohol for 3 hours, n) treatment of the resulting amine with compound 37 in NaHCOs / H ^ 0, and m) hydrolysis of the resulting bis-acetoxy compound using K2C03 in MeOH for obtain the aldehyde The resulting aldehyde (35 mg, 0602 mmol), hydroxylamino hydrochloride (NH20H-HC1) (86 mg, 12 mmol), and Et3N (2 eq) in MeOH (5 mL) were stirred for 24 hours at room temperature Then the reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed with brine (2 x 20 mL) The combined organic layer was dried over anhydrous Na: jS04 and concentrated The purification of the resulting crude product by chromatography on flash silica gel provided the azido oxime as an oil The azide function of the oxime was hydrogen on Pd / C (10%) in MeOH for 6 hours, and the resulting amine was treated with compound 15 (1 eq) and Et3N (2 eq) in CH2C12 for 3 hours to obtain Compound 120 as a solid lH NMR (CDC13, 400 MHz) d 8 15 and 8 05 (two s, 2H), 77 (d, 1H, J = 7 6 Hz), 7 72 (d, 1H, J = 7 6 Hz), 7 54 (dd, 1H, J = 7 6 Hz, 8 0 Hz), 5 67 (d, 1H, J = 5 2 Hz), 5 05 (m, 2H), 3 7-4 ( m, 6H), 3 19 (m, 1H), 3 1 (m, 2H), 2 95 (d, 2H, J = 7 6 Hz), 2 8 (dd, 1H, J = 7 6 Hz, 12 4 Hz), 1 6, 1 7 and 1 85 (three m, 3H), 0 89 (d, 6H, J = 6 4 Hz) Compound 121 A (Et O) P (O) C H2CO-E t (1 1 equiv) in THF was added NaH (37 mg, 0.93 mmol), followed by stirring for 10 hours at room temperature. Then aldehyde 116 (222 mg, 0.54 mmol) in THF (2 mL) was added and stirring was continued for 10 minutes at room temperature The reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed with brine (2: |: 20 mL) The combined organic layer was dried over Na2SO, anhydrous and concentrated. Purification of the resulting crude product by flash silica gel chromatography afforded an ester Al ester (50 q, 0 1 mmol) in CH? C12 (5 mL) was added DIBAL-H (diisobutylaluminum hydride) (1M, 0 5 mL) at -78 ° C After 30 minutes, the reaction mixture was warmed to room temperature, then treated with MeOH (1 mL ) to destroy excess DIBAL-H Cold dilute hydrochloric acid (HC1) (10%, 15 mL) was carefully added and the resulting mixture was stirred until a clear organic layer was obtained and extracted with EtOAc (2 x 10 mL). ) The organic layer was washed with brine (2 x 20 mL) The combined organic layer was dried over anhydrous Na2SCu and concentrated to obtain an aminoalicylic alcohol as crude product The amino alcohol (1 equiv), compound 15 (1 equiv) , and Et3N (2 equiv) in CH2C12 were stirred for 3 hours at room temperature. Then the reaction mixture was diluted with EtOAc and the organic layer was washed with brine. The combined organic layer was dried over anhydrous Na-SOj and concentrated. Purification of the resulting crude product by chromatography on silica gel in The present invention provides compound 121 as a solid NMR (CDC13)., 400 MHz) d 7 72 (d, 2H, J = 8 Hz), 7 5 (d, 2H, J = 8 Hz), 7 29 (m, 5H), 6 69 (d, 1H, J = 16 Hz ), 6 51 (m, 1H), 5 6 (d, 1H, J = 5 2 Hz), 5 (m, 1H), 4 95 (d, 1H, J = 8 4 Hz), 4 37 (d, 2H, J = 4 4 Hz), 3 86 (m, 4H), 3 65 (m, 2H), 3 15 (m, 1H), 3 1 (dd, 1H, J = 4 Hz, 14 4 Hz), 3 (m, 2H), 2 81 (m, 2H), 1 45, 1 61, and 1 8 (three m, 3H), 0 91 (ABq, 6H, J = 6 4 Hz) o2 Explanation a) iBuNH, íPrOH, reflux, 6 hours, b) chloride of s 1 f or n 11 or 35, to H CO 3 aqueous, CH2C12, 12 hours, c) H-, Pd-C. { 10%), mixed carbonate 4, Et3N, THF, 12 hours, d) K :: C03, MeOH, 30 minutes, e) reductive amination (NaCNBH.i, AcOH, MeOH), with NH ^ OAc for compound 125, with M e NH for compound 126, with dimet 11 a 1 na (Me: NH) for compound 127, f) NH.OH "HCl, Et 3 N, MeOH, for compound 128, g) RSC CI, where R is 4-hydroxymethoxy-11-chloro-1-chloride, or TsCl, or 8-chloro-1-unsaturated chloride, or benzyl-sulphonyl chloride, aqueous NaHC03, CH2C12, 12 hours, h) Ph3P, THF water, 12 hours 125 1 1 126 127 128 0 53 Compound 125 Compound 124 was converted to compound 125 using the following reaction sequence i) reduction with aBH4 of aldehyde 124 for the primary alcohol, n) tosylation of the primary alcohol, m) nucleophilic displacement of the sulfonate ester with Na 3 / DMF / heat (65 ° C), iv) conversion of the azide function to the amine using Ph3P / THFH20 (9 1) / 12 hours, to obtain the compound 125 XH NMR (CDC13, 400 MHz) d 7 74 (d, 2H, J = 8 4 H?), 7 48 (d, 2H, J = 8 4 Hz), 7 3 (m, 5 H), 4 9 (m, 2 H), 4 41 (m, 1 H), 4 (s, 2 H), 3 78 (m, 3 H), 3 68 (m, 1 H), 2 72-3 2 (m, 6 H), 2 65 (m, 1 H), 2 46 (br s, 2 H) , 1 8-2 1 (m, 5H), 1 4 (m, 2H), 0 88 (ABq, 6H, J = 6 4 Hz) Compound 126 aldehyde 124 (50 mg, 0.89 mmol) and MeNH; (120 mg, 40% in water) in MeOH (5 mL) were stirred in the presence of hydrogen for 12 hours at room temperature Then the reaction mixture was filtered and concentrated The purification of the resulting crude product by gel chromatography instant silica provided compound 126 (39 mg) as a solid H NMR (CDCl 3, 400 MHz) d 73 (d, 2 H, J = 6 8 Hz), 7 47 (d, 2 H, J = 7 6 Hz) , 7 25 (m, 5H), 4 86 (m, 1H), 4 79 (d, 1H, J = 7 6 Hz), 4 39 (t, 1H, J = 6 4 Hz), 3 82 (s, 2H), 3 82 (m, 3H), 3 7 (m, 1H), 3 (m, 4H), 2 8 (ra, 2H), 2 62 (m, 1H), 2 5 (s, 3H), 2 (m, 4H), 1 85 (m, 2H), 1 4 and 1 6 (two m, 2H) r 0 89 (ABq, 6H, J = 6 4 Hz) Compound 127 aldehyde 124 (32 mg, 0 076 mmol) and HNMe2 (0 09 mL, 0 019 mmol) in MeOH (5 mL) was hydrogen in the presence of Pd-C (10%, 10 mg) for 12 hours. Filtration, followed by concentration, gave a crude product. purification of the resulting crude product by flash silica gel chromatography afforded compound 127 (27 mg) as a solid [a] D25 + 19 29, c 0 57, CHC13: H NMR (CDC13, 200 MHz) d 7 78 (d , 2H, J = 8 2 Hz), 7 58 (d, 2H, J = 8 2 Hz), 7 25 (m, 5H), 4 84 (m, 2H), 4 39 (dt, 1H, J = 6 4 Hz, 4 4 Hz), 3 6-3 85 (m, 6H), 2 75-3 2 (m, 6H), 2 6 (m, 1H), 2 38 (s, 6H), 2 (m, 3H), 1 9 and 1 5 (two m, 4H), 0 88 (ABq, 6H, J = 6 4 Hz) Compound 128 aldehyde 124 (137 mg, 0 339 mmol), NH: 0H "HC1 (46 mg, 0.67 mmol), and Et3N (68 mg, 0.67 mmol) in MeOH (5 mL) were stirred for 12 hours at room temperature Then the The reaction mixture was diluted with EtOAc (30 mL) and the organic layer was washed with brine (2 x 20 mL) The combined organic layer was dried over anhydrous Na2SC and concentrated The purification of the resulting crude product by chromatography on silica gel Instantaneously gave compound 128 (84 mg) as a solid 1 H NMR (CDC 13, 300 MHz) 8 8 53 and 8 1 (two s, 2 H), 7 73 (d, 2 Hr J = 8 4 Hz), 7 65 (d , 2H, J = 8 7 Hz), 7 2 (m, 5H), 4 83 (m, 1H), 4 79 (d, 1H, J = 8 7 Hz), 4 35 (m, 1H), 3 78 (m, 3H), 3 61 (m, 1H), 2 75-3 12 (m, 6H), 2 6 (m, 1H), 1 4, 1 8, and 2 (three m, total 7H), 0 83 (ABq, 6H, J = 6 4 Hz) Compound 129 Compound 37 was used in place of compound 35 in the reaction sequence as was described for compound 124 to obtain the corresponding meta-substituted aldehyde in quantitative yield The aldehyde was subjected to similar conditions as described for compound 128 to obtain compound 129 as a solid in quantitative yield] H NMR (CDC13, 400 MHz ) 6 9 5 (s, 1H), 8 1 (s, 2H), 7 77 (d, 1H, J = 8 Hz), 7 62 (d, 1H, J = 7 6 Hz), 7 55 (t, 1H, J = 4 Hz) , 7 23 (m, 5H), 5 02 (d, 1H, J = 8 8 Hz), 4 94 (m, 1H), 4 44 (m, 1H), 3 6-4 (m, 4H), 3 4, 3, and 2 83 (three m, 6H), 2 65 (m, 1H), 2 05 (m, 4H), 1 5, 1 63, and 1 9 (three m, 3H), 0 89 (ABq, 6H, J = 6 4 Hz) Compound 130 to 4-bromobenzyl alcohol (1 equiv) in THF was added sodium hydride (to H) (2 equiv) at 0 ° C to sodium alkoxide After 20 minutes, methyl iodide (Mel) (4 equiv) was added, and the reaction mixture was allowed to stir for 24 hours at room temperature. After work and purification, n-BuLi (2 1 equiv) was used to the resulting methylether derivative in THF at -78 ° C, followed by stirring for 1 hour In another flask, S02C1 (5 equiv) in THF was charged and cooled to -78 ° C. This solution was added to the previous solution after one hour, working with saturated NH4C1 solution and flash chromatography, p-methyl chloride was provided with 11 percent strength or 33% yield. After step (a) in the above scheme, the resulting amine (1 equiv), the chloride of p-met or ímet i lbencensu 1 f on i 1 or earlier (1 1 equiv) and Et3 (2 equiv) in CH2C12 were stirred for 12 hours at room temperature The washing of the reaction mixture with brine and NH, C1 saturated, and the purification of crude residue, provided the corresponding sulfonamide The azido function of the sulfonamide was converted to the amine using Ph3P / TH «H20 (9 1) / 12 hours After purification, the resulting amine (1 equiv), the active carbonate 4 (1 1 equiv), and Et ?N (2 equiv) in CH CI2 were stirred for 2 hours at room temperature. Then the reaction mixture was diluted with EtOAc and the organic layer was washed with brine. The combined organic layer was dried over Na + SC. anhydrous and concentrated The purification of the resulting crude product by flash silica gel chromatography afforded compound 130 as an H NMR liquid (CDC13, 400 MHz) d 7 76 (d, 2H, J = 8 4 Hz), 7 48 (d, 2H, J = 8 4 Hz), 7 27 (m, 5H), 3 8 (m, 3H), 3 63 (m, 1H), 3 43 (s, 3H), 3-3 15 (m, 3H), 2 95 (dd, 1H, J = 13 6 Hz, 8 4 Hz), 2 83 (m, 2H), 2 63 (m, 1H), 2 05 (m, 3H), 1 81 (m, 2H), 1 49 and 1 55 (two m, 2H), 0 87 (ABq, 6H, J = 6 4 Hz) Compound 131 After step (a) in the above scheme, the resulting amine (1 equiv) and TsCl (1 1 equiv), in a mixture of saturated solution of N to HCO3 and CH¾C 1.-:, were stirred for 12 hours at room temperature. Then the reaction mixture was extracted with EtOAc and the organic layer was washed with brine. The combined organic layer was dried over anhydrous N a 2 S O 4 and concentrated. Purification of the resulting crude product by flash silica gel chromatography provided the β-toluensulphonamide derivative. The azido function of the above sulfonamide was hydrogen in the presence of Pd-C (10%) for 6 hours and the resulting amine (1 equiv), active carbonate 4 (11 equiv), Et 3 N (2 equiv) in CH 2 C 12 were stirred for 4 hours at room temperature. Then the reaction mixture was I dilute with EtOAc and the organic layer was washed with brine The combined organic layer was dried over anhydrous Na2SO4 and concentrated The purification of the resulting crude product by flash silica gel chromatography afforded compound 131 as a solid XH NMR (CDC15, 400 MHz) 6 7 6 (d, 2H, J = 8 4 Hz), 7 31 (d, 2H, J = 8 Hz), 7 25 (m, 5H), 4 87 (m, 1H), 4 75 (m, 1H), 4 4 (m, 1H), 3 8 (m, 3H), 3 7 (m, 1H), 2 7-3 2 (m, 6H), 2 62 (m, 1H), 2 42 (s, 3H), 2 03 (m, 3H), 1 82 (m, 2H), 1 4 and 1 53 (two m, 2H), 0 87 (ABq, 6H, J = 6 4 Hz) Compound 132 After step (a) in the above scheme, the resulting amine (1 equiv) and the commercially available 8-quinolmsulfonyl chloride (11 equiv) in a mixture of a saturated NaHCO ^ solution and CH: .C12 were stirred for 12 hours at room temperature. the reaction mixture was diluted with EtOAc and the organic layer was washed with brine. The combined organic layer was dried over anhydrous NaS SC and concentrated. n of the resulting crude product by flash silica gel chromatography provided the corresponding 8-qu i no 11 n s 1 f onamide derivative The azido function of the above qumolm derivative (7 mg, 0.016 mmol) was hydrogen in the presence of Pd-C (10%) in THF for 6 hours, and the resulting amine was treated in situ with active carbonate 4 (4 mg, 0 016 mmol) and Et3 (2 equiv) in CH-CI2 (2mL) The resulting mixture was stirred for 2 hours at room temperature. Then the reaction mixture was diluted with EtOAc and the organic layer was washed with brine. The combined organic layer was dried over anhydrous Na2SO and concentrated. crude product resulting by flash silica gel chromatography provided compound 132 (6 mg) as a solid? NMR (CDC13, 300 MHz) d 9 02 (dd, 1H, J = l 8 Hz, 3 9 Hz), 8 51 (dd, 1H, J = 0 92 Hz, 7 2 Hz), 8 23 (dd, 1H , J = 1 8 Hz, 8 7 Hz), 8 03 (dd, 1H, J = 0 9 Hz, 8 1 Hz), 7 6 (dd, 1H, J = 7 5 Hz, 7 8 Hz), 7 53 (dd, 1H, J = 4 5 Hz, 8 4 Hz), 7 2 (m, 5H), 4 8 (m, 1H), 4 73 (d, 1H, J = 7 8 Hz), 4 34 (dd , 1H, J = 5 4 Hz, 6 3 Hz), 3 76-3 92 (m, 3H), 3 6 (m, 1H), 3 29 (d, 1H, 14 Hz), 3 02 (m, 3H ), 2 91 (m, 2H), 2 62 (m, 1H), 1 97 (m, 3H), 1 7 (m, 2H), 1 52 and 1 4 (two m, 2H), O 65 (ABq , 6H, J = 6 4 Hz) Compound 133 After reaction step (a), the resulting amine (41 mg, 0.157 mmol), the benzyl chloride 11 its 1 f oni is commercially available (11 equiv), and Et3N (2 equiv) in CH2C12 (3 raL) were stirred for 12 hours at room temperature. Then the reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed with brine (20 mL). The combined organic layer was dry on Na2SC >4 anhydrous and concentrated The purification of the resulting crude product by flash silica gel chromatography provided the corresponding sulfonamide. The above sulfonamide (38 mg. 0 091 mmol) and Ph3P (47 mg, 0 18 mmol) in THF «H20 (9 1) were stirred for 12 hours at room temperature. Then the reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed with water. brine (20 mL) The combined organic layer was dried over anhydrous N.sub.2 SO.sub.4 and concentrated The resulting crude amine product, active carbonate 4 (25 mg, 0.93 mmol), and (2 equiv) in CH2C12 ( 5mL) were stirred for 4 hours at room temperature. Then the reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed with brine (20 mL). The combined organic layer was dried over anhydrous Na SC and concentrated. Purification of the resulting crude product by flash silica gel chromatography gave compound 133 as a solid * H NMR (CDC13, 400 MHz) 6 7 18-7 36 (m, 10H), 4 9, 4 73, and 4 4 (three m, 3H), 4 27 (s, 2H), 3 72 (m, 4H), 3 05 and 3 16 (two m, 2H), 2 81 ( m, 5H), 1 5-2 1 (m, 7H), 0 84 ABq, 6, H, J = 6 4 Hz) Compound 134 After reaction step (a), the resulting amine (1 equiv), 3,5-dihydroxybenzoic acid (1 equiv), EDCI (1 - (3-dimime 111 aminopropyl 1) - 3 -et 11 ca rbodi amide hydrochloride) (1 2 equiv), HOBt (1 -hi dr oxiben z ot r) hydrated iodine) (1 2 equiv), and Et 3 N (4 equiv) in (9 1) were stirred for 12 hours at room temperature. Then the reaction mixture was diluted with EtOAc and the organic layer was washed with brine. The organic layer The mixture was dried over anhydrous Na-SCu and concentrated The purification of the resulting crude product by flash silica gel chromatography provided the corresponding 3,5-dihydroxybenzamide derivative The above derivative (1 equiv) and the active carbonate 4 (1.1 equiv. ) in THF were stirred under a hydrogen atmosphere in the presence of Pd-C (10% ) for 12 hours at room temperature Then the reaction mixture was filtered and the organic layer was washed with brine The combined organic layer was dried over anhydrous N 2 SO 4 and concentrated The purification of the resulting crude product by flash silica gel chromatography I provide compound 134 as a solid Explanation a) Isobutylamine, isopropanol, reflux, 6 hours, b) sulfonyl chloride 35, N to HC03 aqueous, CH2C1, c) K2C03r MeOH, 30 minutes, d) N -methylpyrazma or morpholine, NaCNBH, AcOH, MeOH, 12 hours , e) TFA, CH2C12, f) mixed carbonate 22, E13, CH2C12 Compound 137 XH NMR ÍCDC1 < , 400 MHz) or 7 71 (d, 2H, J = 8 Hz), 7 47 (d, 2H, 8 4 Hz), 7 27 (m, 5H), 4 65 (d, 1H, J = 8 4 Hz ), 3 79 (m, 2H), 3 55 (s, 2H), 2 8-3 12 (m, 6H), 2 5 (br m, 8H), 2 31 (s, 3H), 1 84 (m , 1H), 1 33 (s, 9H), 0 9 (ABq, 6H, J = 6 4 Hz) Compound 138 compound 125 was subjected to TFA »CH2C1- (20%) for 20 minutes at room temperature, which gave a crude amine salt after concentration. The amine salt (8.7 mg), the active carbonate 22 ( 5 mq), and Et3 (2 equiv) in CH2C12 (2 mL) were stirred for 4 hours at rearing temperature. Then the reaction mixture was diluted with EtOAc (20 rtiL) and the organic layer was washed with brine (20 mL). The combined organic layer was dried over a2SO, j anhydrous and concentrated. Purification of the resulting crude product by flash silica gel chromatography afforded compound 138 ~ H MMR (CDC13., 400 MHz) d 7 74 (d, 2H, J = 8 Hz], 7 51 (d, 2H, J = 8 4 Hz), 7 29 (m, 5H), 5 11 (m, 1H), 4 88 (d, 1H, J = 8 4 Hz), 3 79 (m, 5H), 3 61 (m, 1H), 3 56 (s, 2H), 3 12 (m, 1H), 2 95 (d, 2H, J = 13 6), 2 92 and 2 87 (two m, 2H), 2 82 (dd, 1H, J = 6 8 Hz, 13 6 Hz), 2 5 (m, 8H), 2 37 (s, 3H), 2 1, 1 92, and 1 81 (three m, 3H), 0 88 (ABq, 6H, J = 6 4 Hz) Compound 139 to compound 135 (17 mg), AcOH (3 mg), and morpholm (9 mg) in MeOH was added NaCNBH4 (4 mg) The resulting reaction mixture was stirred for 12 hours at room temperature Then the reaction mixture was Dilute with EtOAc (20 mL) and wash the organic layer with brine (2 x 20 mL) The combined organic layer is dried over anhydrous NaHCO3 and concentrated The purification of the resulting crude product by chromatography on silica gel The morpholine derivative was provided with morpholine derivative (10 mg) treated with 20% TFA (acid tr 1 f 1 or co 1 co) H2C12 (3 mL) for 30 minutes after evaporation of the solvent and drying, the resulting amine salt, active carbonate 22 (6 mg) and Et3 (2 equiv) in CH2Cl2 (3 mL) were stirred for 3 hours at room temperature. Then the reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed with brine (20 mL) The combined organic layer was dried over anhydrous NaSO 4 and concentrated The purification of the resulting crude product by flash silica gel chromatography afforded compound 139 LH NMR (CDCl 3, 400 MHz) d 7 75 (d, 2 H, J = 8 Hz), 7 5 (d, 2 H, J = 8 Hz), 5 1 (m, 1 H), 4 88 (d, 1 H, J = 8 4 Hz), 3 8 (m, 9H), 3 6 (m, 1H), 3 55 (s, 2H), 3 14 (dd, 1H, J = 7 6 Hz, 15 2 Hz), 3 05 ( m, 3H), 2 91 (m, 1H), 2 88 (dd, 1H, J = 6 4 Hz, 13 2 Hz), 2 5 (s, 4H), 2 1, 1 9, and 1 87 (three m, 3H), 0 89 (ABq, 6H, J = 6 4 Hz) ?? IC50 Ki or (nM) (nM) 150 540 i52 i53 i55 ??? ??? ?? 160 ?? ?? i63 i64 ?? ??? 251 252 BocHN. 1-PrOH, compound 252 12 hours Ph ' EtOH, 3 Angstroms MS Me2CHCHO,? 12 hours 252a 15 22 3S-Aminop.Lrrol.Ld.in-2 -one (252) A solution of hydrochloride of the acid (S) - - ammo - 2 - met i lbut iric (251, 190 mq, 1 23 ramol) in acetonitrile (25 mL) and hexame ti ldi if the anus (HMDS) (1 mL) was heated under reflux for 72 hours The solvent was evaporated under vacuum, and the residue was purified by silica gel column chromatography eluting with 15% MeOH in CHC13 , with a yield of 36 mg of compound 252 (29%) as a colorless solid, Rf = 0 20 Ter-butyl ester of the acid. { 1-Benzyl-2R-hydroxy-3 - [(3 'S) -oxopyrrolidin-3-ylammon] propyl} carbamic (252a) A solution of tert-butyl [S- (R *, R *)] - (-) - (l-oxiranyl-2-phenylethi 1) carbamate (26 mg, 0 10 mmol), 3S-ammopyrrolidin- 2-one (252, 20 mg, 0 20 mmol), and 1 sopropi 1 and 11 amine (70 pL, 0 40 mmol) in isopropanol (3 raL) was heated under reflux for 12 hours The solvent was evaporated under vacuum, and the residue was purified by silica gel column chromatography eluting with 15% MeOH in chloroform (CHC13), in 10 mg yield of compound 252a (28%) as a colorless solid, Rf = 0 25 Ter-but-ester of the acid . { 1 S-benzyl-2R-hydroxy-3- [(3 'S) -isobutyl (2-oxopyrrolidin-3-yl) amino] propyl} carbamic (252b) A solution of ter-butilester of the acid. { 1 S -benz 11-2 R-h 1 droxy-3 - [(3 'S) -oxopyrrolidin-3-ylamino] propyl (carbamic (252a, 5 0 mg, 0 014 mmol), iso-butyraldehyde (0 10) , 1 1 mmol), and molecular sieve (3A, 100 mg) in EtOH (1 mL) under argon was heated to reflux for 12 hours. The solvent was evaporated under vacuum, and the residue was redissolved in EtOH (1 mL) Ice-cold acetic acid (0 10 mL) was added, followed by sodium cyanoborohydride (30 mg, 0 048 mmol) After 30 minutes, saturated aqueous HCOj (5 mL) was added, and the mixture was extracted with CHC13 (3 x). 10 mL) The organic layer was dried, evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel eluting with 5% MeOH in CHC13, giving 4.9 mg of compound 252b (85%) as a solid colorless, Rf = 0 22 Compound 248 A solution of tert-butyl ester of the acid { lS-benzyl-2R-hydroxy-3- [(3r S) isobutyl- (2-oxopyrrolidm-3-yl) -amino] propi 1 .}. ca r ami co (252b, 5 0 mg, 0 012 mmol) in 20% TfA in CH2C12 (5 mL) was stirred for 30 minutes. The reaction mixture was then concentrated and redissolved CHCl? (5 mL) To this solution was added triethylamine (0 1 mL), and, after 5 minutes, carbamate 22 (3.0 mg, 0 013 mmol) After stirring for 20 minutes, the solvent was evaporated under vacuum, and the The residue was purified by column chromatography on silica gel eluting with 5% MeOH in CHC1: > , giving 4 5 mg of compound 248 (86%) as a colorless solid, Rr = O 15 ^ -NMR (400 MHz, CDC13) d 7 29-7 17 (m, 5H), 6 05 (bs, 1H) , 5 10 (bs, 1H), 4 88 (d, 1H, J = 9 3 Hz), 3 84-3 63 (m, 7H), 3 34-3 28 (m, 2H), 2 93-2 87 (m, 2H), 2 46-2 43 (m, 2H), 2 31-2 05 (m, 4H), 1 95-1 87 (ra, 2H), 1 77-1 70 (m, 1H), 0 94 (d, 3H, J = 6 4 Hz), 0 87 (d, 3H, J = 6 4 Hz Compound 249 A solution of tert-butyl ester of the acid { LS-benzyl-2R-hydroxy-3- [ (3 'S) -isobutyl (2-oxopyrrolidin-3-yl) -ammo] propi 1.} Carbamate (252b, 50 mg, 0 012 mmol) in 20% TFA in CH2C12 (5 mL) was stirred for 30 minutes The reaction mixture was then concentrated and redissolved in CH 2 Cl 2 (5 mL) To this solution was added t riet 1 sheet (0 1 mL), and, after 5 minutes, carbamate 15 (3 4 mg, 0 013 mmol) After stirring for 20 minutes, the solvent was evaporated under vacuum, and the residue was purified by column chromatography on silica gel eluting with 5% MeOH in CH CI 3, providing 3 8 mg of compound 249 (67%) as a colorless solid, Rf = 0 25 1 H-NMR (400 MHz, CDC 13) d 7 26-7 16 (m, 5H), 5 63 (d, 1H, J = 5 2 Hz), 5 10 (bs, 1H), 5 00-4 97 (m, 1H), 3 98-3 92 (m, 2H), 3 86- 3 72 (m, 2H), 3 71-3 61 (ra, 5H), 3 40-3 25 (m, 2H), 3 05-2 95 (m, 1H), 2 92-2 81 (m, 1H ), 2 75-2 69 (m, 1H), 2 53-2 37 (m, 2H), 2 33-2 18 (m, 2H), 1 95-1 83 (m, 2H), 1 1 52 ( m, 3H), 0 95 (d, 3H, J = 6 2 Hz), 0 88 (d, J = 5 4 Hz) 3-Isobutylimino-l, 3-dihydro-indol-2-one (245) To a stirred suspension of isatma (5 00 g) in absolute EtOH (40 mL) was added obu 111 amine (3 7 mL) at 23 ° C and the mixture was stirred for 4 hours. The mixture was then filtered, and a light yellow solid was collected and recrystallized from EtOH to provide 2 32 g, 34%, of light yellow cells. a mixture of geometrical isomers in an approximate 2 1 1 H -NMR (300 MHz, CDC13) d 10 05 (bs, greater), 9 0 (bs, lower), 7 67 (d, J = 7 2 Hz, higher ), 7 62 (d, J = 7 2 Hz, lower), 7 34 (m, 2H), 7 04 (m, 3H), 7 86 (d, J = 7 8 Hz, lower), 4 19 (d , J = 6 9 Hz, lower), 3 82 (d, J = 6 9 H ?, higher), 2 31 (m, higher), 2 12 (m, lower), 1 08 (d, J = 6 3 Hz, higher), 1 03 (d, J = 6 9 Hz, lower), 13 C-NMR (75 MHz, CDC13) d 165 8, 154 6, 145 0, 133 3, 132 5, 127 1, 122 9, 122 2, 117 4, 111 9, 110 5, 62 3, 59 8, 30 5, 30 1, 21 0, 20 7 3 - I s obu 11 ami no - 1, 3 - dihi dr o - i ndo 1 - 2 - or na (246) To a solution of λ 255 (3.0 g) in EtOAc (50 mL) was added 10% Pd / C (0 10 g), and the mixture was hydrogenated under a sphere for 8 hours. The mixture was filtered through of a celite pad and concentrated m vacuo to provide a whitish solid To this solid was added 100 mL of anhydrous diethyl ether-HCl solution and the mixture was stirred for 10 minutes. The resulting bright pink salt was filtered under recr The reaction was carried out with ether from EtOH to give 2 2 g (61%) of 3-1 s hydrochloride obut 11 ami no-1,3-dihydro-1 ndo 1 -2-one 1 H-NMR ( 300 MHz, CD3OD) d 7 67 (d, J = 8 1 Hz, 1H), 7 41 (t, J = 7 8 Hz, 1H), 7 14 (t, J = 7 8 Hz, 1H), 7 00 (d, J = 7 8 Hz, 1H), 5 07 (s, 1H), 3 06 (dd, J = 12 0, 7 2 Hz, 1H), 2 91 (dd, J = 12 0, 6 9 Hz , 1H), 2 08 (m, 1H), 1 04 (d, J = l 8 Hz, 3H), 1 02 (d, J = l 5 Hz, 3H), 13C-NMR (75 MHz, CD3OD) d 172 9, 144 7, 132 5, 127 3, 124 2, 121 5, 112 1, 58 5, 53 4, 27 5, 20 4 The hydrochloride salt was converted to the free amine immediately before being used in the next reaction for washing with NaHCO 3 and extracted with CH C12 1 H-NMR (300 MHz, CDC13) d 9 62 (s, 1H), 7 35 (d, J = 7 5 Hz , 1H), 7 21 (t, J = 7 5 Hz, 1H), 7 03 (t, J = 7 2 Hz, 1H), 6 89 (d, J = 7 8 Hz, 1H), 4 39 (s , 1H), 2 41 (dd, J = 10 5, 6 6 Hz), 2 20 (dd, J = 10 5, 6 9 Hz), 1 67 (m, 1H), 0 88 (d, J = 2 4 Hz, 3H), 0 86 (d, J = 2 4 Hz, 3H) Peaks at 2 41 and 2 20 combined during 3H due to the portion of few NH, 1 C-NMR (75 MHz, CDC13) d 180 4 , 141 7, 128 8, 127 6, 125 0, 122 6, 110 2, 61 0, 52 7, 28 9, 20 6, 20 5 (2R, 3S) -3- [(3-Azido-2-hydroxy -4-phenyl-butyl) -isobutyl-ammo] -1,3-dihydro-mdol-2-one (247) was added to a solution of (2 R, 3 S) -2- (1 -z-ido-2) - fen- i 1 -et i 1) oxir anus (64) (16 2 mg) in isopropanol (2 mL) was cold-washed 3- i sobut i 1 ami no-1,3-dihydro-indol-2-one (15.4 mg), and the solution was refluxed for 22 hours. The mixture was cooled and the solvent was illuminated under pressure. reduced The column on flash chromatography (40, 70% EtOAc / hexane) provided the alcohol azido (12.4 mg, 37%) as a mixture of diastereomers at 2 1 1 H-NMR (300 MHz, CDC13) d 7 99 (s, minor), 7 77 (s, greater), 7 37 (d, J = 7 8 Hz), 7 32-7 20 (m), 7 12-7 05 (m), 6 89 (t, J = 7 5 Hz, 2H), 4 46 (s, minor), 4 43 (s, greater), 4 30 (bs, greater), 4 04 (bs, minor), 3 82-3 76 (m), 3 65-3 59 (m), 3 56-3 53 (m), 3 30 (dd, J = 12 9, 2 4 Hz), 3 00-2 91 (m), 2 76-2 69 (m), 2 60- 2 47 (m), 2 07-1 99 (m), 1 84-1 80 (m), 1 59 (s, minor), 1 28-1 23 (m), 0 97-0 85 (m) Compound 250 To a solution of azide 247 THF in dry (2 mL) was added mixed carbonate 15 (10 mg), triethylamine (10 μ), and 10% Pd / C (7 6 mg), and the mixture was hydrogen or a sphere for 2 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated m vacuo. The residue was chromatographed on silica gel (60, 100% EtOAc / hexane) of compound 250 as a white solid (10 9 mg, 60%) as a mixture of diaster omeros 1H-NMR (500 MHz, CD3OD) d 7 43 (d, J = 7 5 Hz, 1H), 7 39 (d, J = 7 4 Hz), 7 25-7 13 (m), 7 04 (t, J = 6 8 Hz, 1H), 6 99 (t, J = 7 4 Hz, 1 H), 6 86 (d, J = 7 8 Hz), 5 57 (t, J = 4 9 Hz), 4 56 (s), 4 54 (s), 3 92-3 88 (m ), 3 78-3 63 (m), 3 24-3 22 (m), 3 15 (dd, J = 14 0, 3 6 Hz), 2 96 (dd, J = 13 9, 3 6 Hz), 2 86-2 84 (m), 2 81 (m), 2 77 (d, J = 5 3 Hz), 2 69-2 65 (m), 2 60-2 53 (m), 2 32-2 28 (m), 2 06-2 01 (m), 1 83-1 78 (m), 1 57-1 48 (m), 1 40-1 34 (m), 1 29 (s), 0 93-0 84 (m) ??? ??? 180 301a R b S 02a R 303a b S b S 303a R b S 304a R b S 305a R b S Scheme B Ph ' 304a R b S 309a R b S Scheme C 305a R b S 401a R b S 307a R b S i85 Ter-bu liestei of acid. { (1S) -benoyl- (2R) -hydroxy-3- [(4-methoxybenzenesulfonyl) - (5-oxopyrrolidin- (2R) -ylmethyl) amino] -propyl) carbamic (305a) A solution of the ter-butyl ester of the Acid { (1S) -benzyl- (2R) -hydroxy-3- [(5-oxopyrrolidin- (2R) -i lme t i 1) amino] prop i 1} -carbamic (304a, 19 4 mg, 0 051 mmol) and 4-methoxybenzenesulfonyl chloride (32.0 mg, 0.154) in CH2C12 (4 mL) and saturated aqueous NaHCO3 (4 mL) was stirred overnight at room temperature. The mixture was then extracted with CHC13 (3 x 5 mL). The organic layer was dried over NaSC, and the residue was purified by silica gel column chromatography eluting with 10% MeOH in CHC 1 -, yielding 22 mg of compound 305a (78¾) as a colorless solid, Rf = 0 45 XH NMR (300 MHz, CDC13) d 1 33 (s, 9H), 1 58-1 76 (m, 1H), 2 10-2 26 (m, 1H) , 2 27-2 42 (m, 2H), 2 73-2 83 (m, 1?), 2 84-3 07 (m, 3H), 3 19 (t, 2H, J = 14 4 Hz), 3 70-3 84 (m, 1H), 3 85 (s, 3H), 3 92-4 05 (m, 2H), 4 90 (bs, 1H), 6 95 (d, 2H, J = 9 0 Hz) , 7 18-7 30 (m, 5H), 7 68 (d, 2H, J = 9 0 Hz), 7 37 (bs, 1H) Tert-butylester of the acid ((1S) -benzyl- (2R) -hydroxy-3- [(4-nitrobenzenesulfon-yl) - (5-oxopyrrolidin- (2R) -ylmethyl) amino] propyl) -carbamic acid (307a) A acid ter-butilester solution . { (lS) -benzyl- (2R) -hydroxy-3- [(5-oxopyrrolidin- (2R) -i Imet 11) ammo] propi 1} Carbonaceous (304a, 29 0 mg 0 0768 mraol) and 4-nitric chloride obtained their 1 phonyl (51 0 mg 0 230) in CH2C12 (1 mL) and saturated aqueous NaHCO3 (1 mL) was stirred during the overnight at room temperature The mixture was then extracted with CHCl3 (3 x 5 mL). The organic layer was dried over NaSO4, and the residue was purified by silica gel column chromatography with 6% MeOH in CHC13, providing 38 mg of the compound 307a (88%) as a colorless solid, Rf = 0 20? NMR (400 MHz, CDCl 3) d 1 37 (s, 9H), 1 60-1 74 (m, 1H), 2 23-2 30 (m, 1H), 2 35-2 40 (m, 2H), 2 88-2 93 ( m, 1H), 2 94-3 08 (m, 3H), 3 36-3 42 (m, 2H), 2 67-3 84 (m, 1H), 3 92-4 05 (m, 2H), 4 69 (bs, 1H), 7 20-7 33 (m, 6H), 7 96 (d, 2H, J = 6 8 Hz), 8 36 (d, 2H, J = 6 8 Hz) Compound 273 A solution of the acid-bu tide of the acid. { (1S) -benzyl- (2R) -hydroxy-3- [(4-methoxybenzenesulfonyl) - (5-oxopyrrolidin- (2R) -ylmethyl) amino] propyl} carbamic (305a, 8 2 mg, 0 0150 mmol) in 20% TFA in CH2C12 (5 mL) was stirred for 30 minutes The reaction mixture was then concentrated and redissolved CH2CI2 (2 mL) Triethylamine (0 mL) was added. 00104 mL) to this solution, and after 5 minutes the carbamate 528b (5 7 mg 0 0749 mmol) was added. After stirring for 20 minutes, the solvent was evaporated under vacuum, and the residue was purified by gel column chromatography. silica gel eluting with 5% MeOH in CH2C12, giving 7 7 mg of compound 306a (83%) as a colorless solid, Rf = 0 20 XH NMR (400 MHz, CDCl) d 1 52-1 73 (m, 3H) , 2 15-2 26 (m, 1H), 2 35-2 41 (m, 2H), 2 70-2 78 (m, 1H), 2 81-3 01 (m, 3H), 3 04-3 15 (m, 1H), 3 24-3 31 (m, 2H), 3 61-3 80 (m, 3H), 3 86 (s, 3H), 3 92-4 01 (m, 2H), 4 03- 4 13 (m, 2H), 4 97-5 02 (m, 1H), 5 60 (bs, 1H), 5 61 (d, 1H, J = 5 4 Hz), 6 97 (d, 2H, J = 7 2 Hz), 7 19-7 26 (m, 5H), 7 70 (d, 2H, J = 7 2 Hz), 7 91 (bs, 1H) Compound 274 A solution of the ter-but i lester of the acid. { (lS) -benzyl- (2R) -hydroxy-3- [(4-nitrobenzenesulfonyl) - (5-oxopyrrolid- (2R) -11-methyl) amino] propyl} carbamic (307a, 15.0 mg, 0267 mmol) in 20% of the TFA in CH2C12 (5 mL) was stirred for 30 minutes. The reaction mixture was then concentrated and redissolved CH-Cl; (2 mL) Triethylamine (0 00185 mL) was added to this solution, and after 5 minutes carbamate 28b (10 1 mg, 0 0373 mmol) was added. After stirring for 20 minutes, the solvent was evaporated under vacuum, and the The residue was purified by silica gel column chromatography eluting with 6% CH2Cl2 in CHCl3, providing 13 mg 3 mg of compound 308a (81%) as a colorless solid, R = = 19 lti NMR (500 MHz, CDCl3) d 1 59-1 69 (m, 2H), 1 70-1 80 (m, 1H), 2 18-2 28 (m, 1H), 2 34-2 41 (m, 2H), 2 70-2 77 (m, 1H), 2 88-2 93 (m, 1H), 3 03-3 16 ( m, 3H), 3 22-3 28 (m, 2H), 3 60-3 69 (m, 1 H), 3 71-3 76 (m, 1H), 3 78- 3 83 (m, 1H), 3 91-3 99 (m, 2H) , 4 00-4 12 (m, 2H), 4 99-5 04 (m, 1H), 5 57 (bs, 1H), 5 63 (d, 1H, J = 5 2 Hz), 7 19-7 28 (m, 5H), 7 95 (d, 2H) , J = 8 8 Hz), 8 14 (bs, 1H), 8 36 (d, 2H, J = 8 8 Hz) Compound 276 A solution of compound 308a (20 mg, 0 032 mmol), zinc (65 mg, 0 99 mmol), calcium chloride (CaCl 2) (2 5 mg, 0 023) in ethanol (EtOH) (4 mL), and water (1 mL) were brought to reflux for 5 hours. NaHCO;, saturated aqueous was added. to this mixture (5 mL), then the reaction mixture was extracted with CHC13 (3 x 5 mL). The organic layer was dried over NaSO 4, and the residue was purified by column chromatography on silica gel eluting with 10% strength. MeOH in CHClj, yielding 9.0 mg of compound 309a (47%) as a colorless solid, R; = 0 24 XH NMR (400 MHz, CDC1) 6 1 60-1 69 (m, 2H), 1 73-1 81 (m, 1H), 2 15-2 16 (m, 1H), 2 31-2 41 (m, 2 H), 2 60-2 71 (m, 2 H), 2 72-2 93 (m, 2H ), 3 07-3 11 (m, 1 H), 3 22-3 35 (m, 2H), 3 60-3 72 (m, 2 H), 3 81-3 99 (m, 4H), 4 00 -4 05 (m, 1H), 4 97-5 03 (m, 1H), 5 35 (bs, 1H) , 5 63 (d, 1H, J = 5 2 Hz), 6 66 (d, 2H, J = ll 2 Hz), 8 14 (bs, 1H), 7 19-7 28 (ra, 5H), 7 53 (d, 2H, J = ll 2 Hz) Compound 277 A solution of the ter-butilester of the acid of. { (1S) -benzyl- (2R) -hydroxy-3- [(4-me t or ibencens or l-thionyl) - (5-oxopyrrolidin- (2 R) -i lmet i 1) amino] propi 1} carbamic (305a, 11.0 mg, 0201 mmol) in 20% TFA in CH: C1: (5 mL) was stirred for 30 minutes The reaction mixture was then concentrated and redissolved CH-Clj (2 mL) Triethylamine (0,00084 mL) was added to this solution, and after 5 minutes compound 40 (6 5 mg, 0 024 mmol) was added. After stirring for 20 minutes, the solvent was evaporated under vacuum, and the residue was purified. by column chromatography on silica gel eluting with 5% MeOH in CHC13, affording 6 mg of compound 401a (54%) as a colorless solid, F = 0 22 H NMR (400 MHz) CDCl 3) d 1 46-1 56 (m, 1H), 1 59-1 67 (m, 2H), 1 93-2 08 (m, 3H), 2 18-2 25 (m, 2H), 2 28-2 41 (m, 3H) , 2 60-272 (m, 2H), 2 95-3 22 (m, 5H), 3 54-3 60 (m, 1H), 3 80-3 87 (m, 3H), 3 88 (s, 3H), 3 92-400 (m, 1H), 4 35-4 41 (m, 1H), 4 92 (bs, 1H), 5 33 (m, 1H), 6 99 (d, 2H, J = 8 8 Hz), 7 18-7 29 (m, 5H), 7 71 (d, 2H, J = 8 8 Hz) Compound 279 A solution of the acid-but 11 e s t e r of the acid. { (1S) -benzyl- (2R) -hydroxy-3- [(4-m-benzenesulfonyl) - (5-oxopyrrolidin- (2R) -11 -me t i 1) ami no] prop i 1} ca rbami co (307a, 19 0 mg, 0 0337 mmol) in 20% TFA in CH2C12 (5 mL) was stirred for 30 minutes. The reaction mixture was then concentrated and redissolved CH2C1; (2 mL) Triethylamine (0.00091 mL) was added to this solution, and after 5 minutes compound 400 (12.0 mg, 0.439 mmol) was added. After stirring for 20 minutes, the solvent was evaporated under vacuum, and the residue was purified by silica gel column chromatography eluting with 5% MeOH in CHCl3, giving 16 8 mg of 402a (81%) as a colorless solid, Rf = 0 21 lti NMR (400 MHz, CDC13) d 1 44-1 53 (m, 1H), 1 56-1 62 (m, 2H), 1 90-2 06 (m, 5H), 2 18-2 24 (m, 1H), 2 28-2 41 (m , 2H), 2 60-2 69 (m, 1H), 2 70-2 78 (m, 1H), 2 99-3 22 (m, 4H), 3 23-3 35 (m, 1H), 3 54 -3 62 (m, 1H), 3 80-3 90 (m, 3H), 3 95-4 02 (m, 1H), 4 31-4 40 (m, 1H), 4 91 (bs, 1H), 5 22 (m, 1H), 7 20-7 30 (m, 5H), 7 98 (d, 2H, J = 8 7 Hz), 8 36 (d, 2H, J = 8 7 Hz) (5R) -Hydroxymethylpyrrolidin-2-one (302a) To the acid 5 -oxopy r ro 11 di n - (2 R) -carbox 111 co. { 301a, 5 00 g, 38 7 mmol) in MeOH (50 mL) and DMF (0 5 mL) was added SOCI2 (3 4 mL, 45 5 mmol) dropwise at 0 ° C After stirring overnight, the The solvent was evaporated under vacuum, CHCl3 (70 mL) and saturated NaHCO3 (30 mL) was added, and the mixture was extracted with CHCl3 (3 x 10 mL). The organic layer was dried over NaSCu. Distillation under vacuum (1 mm) provided 3 35 g (60%) of the methylester of 5-oxopyrrolidm- (2R) -carboxylic acidmp 140 ° C Sodium borohydride (44 28 mmol) was added at 0 ° C to this ester (3 17 g, 22 14 mmol) in EtOH (75 mL). After stirring overnight, the reaction mixture inactive with saturated aqueous NH4CI solution The white precipitate was filtered, and the residue was washed with ethyl acetate (EtOAc). Evaporation of the solvent gave 2 30 g (90%) of compound 302a, which was used without further purification JH NMR ( 300 MHz, CDCl) d 1 67-1 79 (m, 1H), 2 03-2 12 (m, 1H), 2 15-2 35 (m, 2H), 3 35-3 43 (m, 1H), 3 56-3 62 (m, 1H), 3 69-3 77 (m, 1H), 4 81 (bs, 1H), 7 55 (bs, 1H) (5R) -Aminomethylpyrrolidin-2-one (303a) To a solution of the (5R) -hydroxymeth-11-pyrrolidin-2-one (302a, 800 g, 6 96 mmol) and Et 3 N (1 94 mL, 13 91 mmol ) in CH2C1 ..: (40 mL) at 0 ° C MsCl (0.591 mL, 7.65 mmol) was added. After stirring overnight, CHCl3 (70 mL) and saturated aqueous NaHCC (30 mL) were added, and The mixture was extracted with CHC13 (6 x 20 mL) and EtOAc (6 x 20 mL). The organic layer was dried over NaSO4, and the residue was purified by silica gel column chromatography on elution with 7% MeOH in CHC13. , providing 864 mg of the corresponding mesylate (65%) as a colorless solid, R £ = 0 21 A solution of this mesylate (0 306 g, 1 60 mmol) and NaN 3 (0 208 g, 3 20 mmol) in DMF (5 mL) was stirred for 6 hours at 80 ° C. Then the solvent was removed, and the residue was purified by silica gel column chromatography eluting with 8% MeOH in CHC13, providing 236 mg of the corresponding azide (98%) as a colorless solid, Rf = 0 30 A solution d e this azide (72.5 mg, 0 518 mmol) in EtOAc (10 mL) was hydrogenated with Pd / C (10%) at 20 psi for 4 hours Filtration through a pad of silica gel (5 g) with MeOH (50 mL) afforded 53 mg of compound 303a (90%): H NMR (300 MHz, CDC13) d 1 64-1 71 (m, 1H), 2 11-2 19 (m, 1H), 2 20- 2 27 (m, 2H), 2 57-2 64 (m, 1H), 2 65-2 77 (m, 1H), 2 81 (bs, 2H), 3 63-3 67 (m, 1H), 7 59 (bs, 1H) Ter-butyl ester of the acid. { (1S) -benzyl- (2R) -hydroxy-3- [(S-oxopyrrolidin- (2R) -limethyl) anino] ropil} carbamic (304a)? n solution of [S - (R +, R *)] - (-) - (1-oxiranyl-2-f-enylethyl) tert-butyl carbamate (2.65 mg, 0 247 mmol) , (5 R) - aminome 11 lp irro 1 ídi n - 2 - one (303a, 120 mg, 0 105 mmol), and di i sop ropi le 11 lamina ((íPr) 2 Et) (0 200 mL, 1 15 mmol) in isopropanol (10 mL) was heated under stirring at 70 ° C for 14 hours. The solvent was evaporated or evacuated, and the residue was purified by silica gel column chromatography eluting with 15% MeOH in CHC1; affording 71 mg of compound 272 (761) as a colorless solid, Rf = 022: H NMR (400 MHz, C DC 13) or 1 34 (s, 9H), 1 63-1 78 (m, 1H), 2 12-2 28 (m, 1H), 2 29-2 38 (m, 2H), 2 53-2 63 (m, 1H), 2 64- 2 73 (m, 1H), 2 74-2 86 (m , 2H), 2 92-3 00 (m, 2H), 3 52- 3 59 (m, 1H), 3 72- 3 90 (m, 2H), 4 88 (d, 1H, J = 9 0 Hz), 7 18-7 22 (m, 3H), 7 26- 7 30 (m, 2H), 7 42 (bs, 1H) Compound 281 A solution of compound 4G2a (15.0 mg, 0.024 mmol), zinc (50 mg, 77 mmol), CaCl2 (2.0 mg, 0.018) in EtOH (1.5 mL), and water (0.5 mL) ) was refluxed for 4 hours. Aqueous saturated NaHC03 (5 mL) was added to this mixture, then the mixture was extracted with CHCl? (3 x 5 mL) The organic layer is dried over Na? S04, and the residue was purified by silica gel column chromatography eluting with 10% MeOH in CHC13, affording 8.0 mg of compound 403a (57%) as a colorless solid, R = = 23: H NMR (400 MHz, C DC 13) d 1 49-1 56 (m, 1H), 1 59-1 64 (m, 2H), 1 83-1 92 (m, 3H), 1 93-2 05 (m, 2H), 2 15-2 27 (m, 1H), 2 30-2 41 (m, 2H), 2 58-2 65 (m, 1H), 2 65-2 73 (m, 1 H), 2 95-3 03 ( m, 1 H), 3 04-3 20 (m, 4H), 3 53-3 62 (m, 1H), 3 78-3 88 (m, 3 H), 3 92-4 0 (m, 1H) , 4 35-4 41 (m, 1H), 4 92 (bs, 1H), 5 38 (m, 1H), 6 67 (d, 2H, J = 8 7 Hz), 7 26-7 36 (m, 5H), 7 54 (d, 2H, J = 8 7 Hz) Compounds 284 and 285 Compound 284 Compound 285 For compounds 284 and 285, RL is defined as hydro or C ^ -alkyl Preferably, Rr is hydro, methyl, or ethyl Compounds 284 and 285 were prepared by the methods described above The ligand is prepared by the method set forth in AD Rao et al, J Indian Chem Soc, 62 3, pages 234-237 (1985) Obviously, many modifications and variations of the invention can be made as shown herein without departing from the spirit and scope of the same, and, therefore, these limitations should only be imposed as indicated by the appended claims

Claims (1)

  1. NOVELTY OF THE INVENTION Having described the present invention, it considers as a novelty and, therefore, claims as property that contained in the following RE IVIND ICAC IONE S A compound having a formula (I) characterized in that R "is selected from the group consisting of C-alkyl, aryl, C i -3-alkyleneheteroaryl, Q 1 'and R "is selected from the group consisting Ci-6alkyl, C2-e.a 1 qui n 11 o, Ci-alkyleneN (Re) he t e roc i c 1 or 1 qui, -NH2, -NHBoc, ( 3alkyleneheterocycloalkyl, optionally substituted with oxo (= 0), (Rd), optionally substituted with oxo. optionally substituted with oxo, N-CH3 N-Boc RJ is selected from the group consisting of ?? 206 or R 'and R3 are taken together to form either an optionally substituted aliphatic monocyclic or bicyclic ring system, or an optionally substituted macrocyclic ring system containing from twelve to twenty atoms, including from one to three heteroatoms selected from oxygen, nitrogen , and sulfur, R4 is selected from the group consisting of hydro and Ci_3a 1 qu 11 enhe t eroc ic 1 or 1 qui 1 o optionally substituted with C (= 0) aryl or C i -3a lqui lena ri lo, X is selected of the group consisting of 0, NRe, S, SO, and S02, A and B, independently, are an aliphatic ring of five, six, or seven members, wherein at least one ring contains one or two of entity X, C is a five or six member aliphatic ring containing one to three of entity X, and is optionally substituted with oxo, Ra is a five or six member aliphatic ring containing one to two of entity X, Rb and R1 -, independently, they are selected from the group consisting of hydro, OH, C -3alkyl, Ct-3a 1 qu 11 enoOH, and Ci_3alqui lenoN (Re) 2, or Rb and Rc are taken together to form an aliphatic ring of five, six, or seven members optionally containing one or two of the entity X, Rd is selected from the group consisting of Ci-4alkyl, C2-fa 1 qu m 11 o, C i - ?, a 1 qu 11 enoC3-sheterocycloalkyl, ORe, C i-] a 1 qu 11 enoORe, N (Re);, SRe, halo, nitro, CHO, cyano, NC, C (= 0) Re, OC (= 0) Rt, C (= 0) 0Re, C (= 0) -N (Re) 2, CH = N0H, CH = CHCH 0H, N (Re) CORe, and Ci_3a 1 qu 11 enN (Re) 2 / or two groups of Rd are taken together to form an aliphatic ring of five, six, or seven members containing optional If one or two of the entity X, Re is selected from the group consisting of the hydro, C1-alkyl, C, -alkynyl, aryl, heteroaryl, C3-8cycloalkyl, THP, Ts, Boc, and C3_ 8heterocycloalkyl , q is 0 to 3, and pharmaceutically acceptable salts, solvates or prodrugs thereof The compound according to claim 1, characterized in that e R ~ is selected from the group consisting of -C (CH3) 3 5 10 fifteen twenty 25 The compound according to claim 1, characterized in that R ~ is selected from the group consisting of OR Y The method according to claim 1, characterized in that R1 is The compound according to claim 1, characterized in that R "is selected from the group consisting of-NH ,, -NHBoc. - (CH-.) - < CH = CH -,, - (CH2) 4C H = CH ~ , CH3 -CH2CH \ CH3 -CH2CH2-N 0 -CH2CH2-N (CH3)? N-CH3 ^ -Boc 10 fifteen 25 The compound according to claim 1 characterized in that R "is selected from the group consisting of - N H2, -NHBoc, - (CH) 3CH = CH; - (CH2) 4CH = CH2, CH 3 / -CH CH \ CH 3 7 The compound according to claim characterized in that R 3 is selected from the group consisting of -so2 The compound according to claim characterized in that R3 is selected from the group consisting of Y The compound according to claim 1, characterized in that R 'and R3 are taken together with the nitrogen atom to which they are attached, to form optionally substituted with C (= 0) NHCi_ galquil, or a macrocyclic ring system containing from 14 to 20 carbon atoms, optionally including SO2, oxygen atoms, or both, and optionally substituted with one or more femlo, benzyl, oxo (= 0) and 0R ~ 10 The compound according to claim 1, characterized in that R'1 is hydroxy The compound according to claim 4, characterized in that Ra independently is selected from the group consisting of CH - ??, NH2, OH, CH3, CH: CH3, CH2NH2, CHO, Cl, F, nitro, OTHP, OCH3, CH2NHCH3, CH = N-OH, and CH2OCH3, or two Rd groups are taken together with the atoms to which they are bound to form The compound according to claim 1, characterized in that the compound has an IC50 value against HIV-1 protease less than about 500 nM The compound according to claim 1, characterized in that the compound has an IC50 value against HIV protease of less than about 20 nM 14 A compound characterized in that it is selected from the group consisting of 223 R = methyl or ethyl ?? wherein Rf is hydro or C i - ¿alkyl 17 The compound according to the claim 16, characterized in that R ee hydro, methyl or ethyl A compound according to claim 1, selected from the group consisting of compounds numbers 75, 78, 79, 87, 88, 99, 100, 113, 114, 117-121 , 125-133, 137-139, 145a, 145d, 146-149, 151-153, 156,157, 163-172, 179, 181-183, 185, 186, 207, 209-213, 253-261, 284, and 285, as set forth herein A compound according to claim 1, selected from the group consisting of compounds numbers 143-145, 154,155, 158-162,188-191 and 200-206, as set forth herein. A compound according to claim 1, selected from the group consisting of compounds numbers 225, 225a-225i, 226, 227 and 229-239, as set forth herein. A compound according to claim 1, selected from the group consisting of the compounds Nos. 248-250, 262-270, 272-275 and 276-283, as set forth herein. A compound according to claim 1, characterized in that it has a structure The compound according to claim characterized in that the group contains from one to three substituents Rd, substituents are independently selected from the group consisting of halo, C2_6alkim, OCF3, N02, CN, CN, N (Re) 2, OR C02Re, C (0) N (Re) 2, C (0) Re, N (Ra) C0R N (Ra) C (O) OR, Ci-3alkylenoORe, and SRe 24 A composition characterized in that it comprises a compound according to claim 1, and a pharmaceutically acceptable diluent or carrier A method for treating a male (male) or female (female) mammal suffering from a condition wherein the inhibition of HIV protease provides a therapeutic benefit which comprises administering to the mammal a therapeutically effective amount of a compound according to claim 1. The method according to claim 25, characterized in that the condition is selected from the group consisting of wild-type HIV and multidrug-resistant HIV. The method according to the indication 25, characterized in that the mammal is a human being. a male (male) or female (female) mammal suffering from a condition wherein the inhibition of the HIV protease provides a therapeutic benefit which comprises administering to the mammal an effective amount of a pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable diluent or carrier 29 A method of trafficking a male (male) or female (female) mammal suffering from a condition wherein inhibition of HIV protease provides a therapeutic benefit comprising administering a therapeutically effective amount of (a) a compound according to claim 1, and (b) a second therapeutically active ingredient useful in the treatment of condition 30 The method according to claim 29, characterized in that (a) and (b) are administered simultaneously, separately, or sequentially. The method according to claim 29, characterized in that the condition is selected from the group consisting of HIV-type HIV and multidrug resistant IH The method according to claim 29, characterized in that the second therapeutically active agent is selected from the group consisting of a second inhibitor of HIV protease, an agent antiviral, an immunomodulator, a nucleoside analog, a tat antagonist, a glucosidase inhibitor, and mixtures thereof 33 The method according to the rei indication 31, characterized in that the second therapeutically active ingredient is selected from the group consisting of Ro 31-859, KNI-272, AZT, DDI, DDC, 3TC, D4T, PMEA, Ro 5-3335, Ro 24-7429, indinavir, ritonavir, saquinavir, nelfinavir, amprenavir, abacavir, castanospremina, castano-spermma, 6-butrilester, - bu 111-1-deoxino] ir -micom, per-butrilester of N-butyl-l-deoxoxjirimycin, 097, acemannan, acyclovir, AD-439, AD-519, adefovir, clipivoxil, AL-721, alpha interferon, ansamicma, beta -f luoro-ddA, BMS-232623, BMS-234475, CI-1012, cidofovir, delaviridin, EL-10, efaviren, famciclovir, FTC, hypericum, Compound Q, ISIS 2922, lobucavir, nevirapine, novapren, T peptide, octapeptide , PNU - 1406 0, probacol, etavudine goes 1 to ci cl ovi r, virazol, zalcitabma, ABT-378, bropi r gamma mterferon, interleukin-2, TNF, etanercept, mfliximab, fluconalzole, piritrexim, trimetrexate, daunorubicma, antagonist of the leukotriene B4 receptor, and analogues and profarans thereof 34 An HIV or AIDS treatment device characterized in that it comprises a compound according to claim 1, or a composition containing a compound according to claim 1, packaged with instructions for administration of the compound, or composition, to a mammal for treating HIV or AIDS A method for inhibiting a retrovirus characterized in that it comprises contacting the retrovirus with a therapeutically active amount Effective of a compound according to claim 1 The method according to claim 35, characterized in that the retrovirus comprises a lentivirus 37 The method according to claim 33, characterized in that the retrovirus is selected from the group consisting of HIV-1, HIV-2, human T-cell leukemia virus, rous sarcoma virus, simian mmunodeficiency virus, feline leukemia virus and feline immunodeficiency virus An article of manufacture characterized in that it comprises (a) a packaged composition comprising a compound according to claim 1, (b) a packaged composition comprising a second pharmaceutical drug useful in a treatment of HIV or AIDS, (c) a separator which provides instructions for simultaneous or sequential administration of (a) and (b) to treat HIV or AIDS in a mammal, and (d) a container for (a), (b) and (c) 39 An article of manufacture characterized in that it comprises (a) a packaged composition comprising a compound according to claim 1, and a second pharmaceutical drug useful in an HIV or AIDS treatment, (b) a separator that provides instructions for the administration of (a) and ( b) to treat HIV or AIDS in a mammal, and (c) a container for (a) and (b)
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MXPA03009179A (en) 2001-04-09 2004-11-22 Tibotec Pharm Ltd Broadspectrum 2-(substituted-amino)-benzoxazole sulfonamide hiv protease inhibitors.
ATE429431T1 (en) 2001-05-11 2009-05-15 Tibotec Pharm Ltd 2-AMINO-BENZOXAZOLE SUPHONAMIDES AS BROAD-SPECTR HIV PROTEASE INHIBITORS
US7157489B2 (en) * 2002-03-12 2007-01-02 The Board Of Trustees Of The University Of Illinois HIV protease inhibitors

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WO2003078438A1 (en) 2003-09-25
JP2006504621A (en) 2006-02-09
US7157489B2 (en) 2007-01-02
US7897635B2 (en) 2011-03-01
CA2478731A1 (en) 2003-09-25
US20040039016A1 (en) 2004-02-26
EP1485387A1 (en) 2004-12-15
AU2003213776A1 (en) 2003-09-29

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